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Evaluations of coronary microvascular dysfunction in a patient with thrombotic microangiopathy and cardiac troponin elevation: a case report

Evaluations of coronary microvascular dysfunction in a patient with thrombotic microangiopathy... Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Evaluations of Coronary Microvascular Dysfunction in a Patient 2 with Thrombotic Microangiopathy and Cardiac Troponin 3 Elevation: A Case Report 1* 1 1,2 5 Kenichiro Otsuka, MD, PhD ; Yasushi Kono, MD, PhD ; Kumiko Hirata, MD, PhD 7 Department of Cardiovascular Medicine, Fujiikai Kashibaseiki Hospital, Kashiba, Japan, 8 Department of Medical Science, Osaka Educational University, Kashiwara, Osaka, Japan 9 https://orcid.org/0000-0001-6780-7034 11 Funding: none 12 Acknowledgement: none 13 Conflicts of interest: none 14 Author contributions: Y.K. prepared the manuscript draft. K.O. conceived study design and 15 prepared the manuscript draft. K.H. supervised the manuscript. 17 *Corresponding author 18 Kenichiro Otsuka 19 Department of Cardiovascular Medicine 20 Fujiikai Kashibaseiki Hospital 21 Address: 3300-3 Anamushi, Kashiba, Japan 22 Tel: +81-745-71-3113 23 Email: otsukakenichiro1@gmail.com © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 2 165x110 mm ( x DPI) 5 Learning Points 6  Thrombotic microangiopathy (TMA) can be life-threatening, and its underlying 7 mechanisms involve platelet aggregation and increased mechanical stress in the 8 microcirculation. 9  Coronary microvascular dysfunction (CMD) caused by TMA contributes to multiple 10 organ failure, myocardial infarction/injury, and sudden cardiac death. 11  Non-invasive assessment of coronary microvascular function and its recovery can 12 provide mechanistic insights into the cardiac involvement in TMA. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Timeline Admission Day 1 Treatment with bi-level positive airway pressure (BiPAP), carperitide, diuretics, and antibiotics in the intensive care unit. Blood culture and urine cultures were performed. Day 2 Transient neurologic deficits. Fresh frozen plasm infusion. Day 3 Treatment with steroid pulse therapy (1 g/day for 3 days), and plasma exchange. Day 5 BiPAP free, treatment with aspirin. Day 6 Prednisolone 40 mg/day. Day 7 TTDE revealed impaired coronary flow reserve (CFR = 1.7). No evidence of an acute infarct area on cardiac magnetic resonance imaging. Day 21 Plasma exchange free, prednisolone 30 mg, renal function improved, move out from high-care unit. Day 22 Invasive coronary angiography. Day 30 Follow-up TTDE demonstrated improved CFR of 2.5. Day 35 Prednisolone 20 mg/day (tapered by 5 mg/week). Day 50 Prednisolone 10 mg/day (tapered by 2.5 mg/2 weeks). Day 90 Antibiotics free, blood culture negative. Day 120 Discharged with prednisolone 5 mg/day after rehabilitation. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Abstract: 2 Background: Thrombotic microangiopathy (TMA) syndromes include thrombotic 3 thrombocytopenic purpura (TTP) and haemolytic uremic syndrome, and contribute to myocardial 4 infarction and multiple organ failure. Although coronary microvascular dysfunction (CMD) is 5 the key for understanding the pathophysiology of cardiac involvement in TMA, there is limited 6 knowledge on the recovery from CMD in patients with TMA. 7 Case summary: An 80-year-old woman was brought to the emergency department due to 8 worsening back pain, dyspnoea on exertion, jaundice, and fever. Although she had typical TTP 9 symptoms and elevated cardiac troponin level, ADAMTS13 activity was preserved (34%), 10 leading to the diagnosis of TMA with myocardial infarction. She underwent plasma exchange 11 and was administered aspirin and prednisolone. Magnetic resonance imaging revealed iliopsoas 12 abscess, which is a possible etiologic factor of sepsis-related TTP. She had impaired coronary 13 flow reserve (CFR) with angiographically nonobstructive epicardial coronary arteries. Improved 14 CFR was observed on follow-up, suggesting existence of transient CMD caused by TMA. After 15 treatment of the iliopsoas abscess with antibiotics for 3 months, she was discharged without any 16 adverse complications. 17 Discussion: CMD is an underlying mechanism of myocardial infarction, with or without 18 epicardial obstructive coronary artery stenosis. TMA is characterised by pathological lesions 19 caused by endothelial cell damage in small terminal arteries and capillaries, with complete or 20 partial occlusion caused by platelet and hyaline thrombi. CMD and its recovery are key for 21 understanding the natural history of cardiac involvement in TMA. In vivo evaluations of CMD 22 can provide mechanistic insights into the cardiac involvement in TMA. 24 Keywords: thrombotic microangiopathy, thrombotic thrombocytopenic purpura, coronary 25 microvascular dysfunction, cardiac troponin, myocardial infarction with nonobstructive coronary 26 arteries, case report ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Introduction 2 Thrombotic microangiopathy (TMA) is a spectrum of life-threatening syndromes, 3 including thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome 4 (HUS). The mechanisms underlying TMA involve platelet aggregation and increased 5 mechanical stress in the microcirculation that contribute to multiple organ failure, including renal 1,2 6 and heart failure, myocardial infarction/injury, and sudden cardiac death. 7 Myocardial infarction/injury is defined by the presence of cardiac troponin elevation 8 caused by structural or functional obstruction of the coronary arteries. In a single centre study, 9 Wahla et al. demonstrated 15.3% of the patients diagnosed with TTP (n = 85) had myocardial 10 infarction. Furthermore, myocardial infarction of the nonobstructive coronary arteries 3,4 11 (MINOCA) can also cause cardiac troponin elevation. Although assessment of the coronary 12 microvascular function is important for understanding the pathophysiology of TMA, there are 13 limited reports on in vivo evaluations of coronary microvascular dysfunction (CMD) and its 14 recovery. Herein, we describe a case of cardiac troponin elevation with CMD associated with 15 TMA, demonstrating non-invasive assessment of the recovery of the coronary microvascular 16 function. 18 Case presentation 19 An 80-year-old woman presented to the emergency department with a 2-week history of 20 worsening back pain, a 5-days history of dyspnoea on exertion, and high temperature. 21 Approximately two weeks before admission she had an episode of back pain and high 22 temperature, and two days before admission she had transient unconsciousness and elevated 23 temperature (40°C). She was a passive smoker on oral antidiabetic medication, and had no 24 documented medical history of prior TTP or autoimmune disorder. On physical examination, she 25 was conscious, had dyspnoea without chest pain, a body temperature of 38.2°C, blood pressure 26 of 106/72 mmHg, pulse of 110 beats/min with 90% oxygen saturation (room air), and bilateral 27 rales; regular heart rhythm; Ⅱ/Ⅵ systolic murmur at apical; distension of the neck veins; 28 jaundice; and petechiae and purpura in her toes. A neurological examination revealed no focal 29 neurologic deficit. Laboratory tests (Table 1) revealed decreased platelet count of 13,000/μL and 30 estimated glomerular filtration rate of 22 ml/min/1.73 mm , increased level of total bilirubin of 31 7.3 mg/dl, increased level of lactate dehydrogenase (LDH) of 812 IU/L, and elevated levels of ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 brain natriuretic peptide and cardiac enzymes (411 IU/L creatine kinase [CK], 40 IU/L CK-MB, 2 and 19,966 pg/mL cardiac troponin I). Chest radiography revealed congestion (Fig. 1a), and a 3 12-lead electrocardiogram on admission showed ST depression in V5 and V6 leads with normal 4 sinus rhythm and a heart rate of 105 beats/min (Fig. 1b). Transthoracic Doppler 5 echocardiography (TTDE) revealed a preserved left ventricular ejection fraction (50%) with 6 hypokinesis of the inferior-posterior wall, suggesting non-ST-segment myocardial infarction. 7 Chest computed tomography (CT) examination revealed lung congestion but no signs of 8 infection. Brain magnetic resonance imaging (MRI) and CT showed no evidence of cerebral 9 haemorrhage (Supplementary Fig. 1a) or infarction (Supplementary Fig. 1b). 10 Considering the severe thrombocytopaenia the management of non-ST-elevation 11 myocardial infarction and heart failure was conservative, with non-invasive respiratory support 12 of the bi-level positive airway pressure, carperitide (0.025 μg/kg/ml), and diuretics (furosemide, 13 20 mg/day), in the intensive care unit. On day 2, the patient had transient neurologic deficits, 14 including 2/5 weakness in both arms, 2/5 weakness in both legs, dysarthria, and 15 unconsciousness. Given the presence of the classic pentad of TTP, including fever, 16 thrombocytopaenia, haemolytic anaemia, renal dysfunction, and neurologic deficit, the initial 17 diagnosis was TTP, and the patient was managed by a multidisciplinary team including 18 specialists from Cardiology, Haematology, Orthopaedics, and Neurology departments. After 19 administration of fresh frozen plasma (FFP) infusion, her platelet count decreased to 6,000/μL 20 with worsening leg purpura (Fig. 2). From day 3 onwards plasma exchange was performed 3 21 times/week. Steroid pulse therapy (1 g/day for 3 days) was administered, followed by high-dose 22 oral steroid therapy (prednisolone 40 mg/day). On day 5, oral aspirin (100 mg/day) was 23 administered, after recovery of her platelet count to >50,000/µL. 24 Spine MRI was performed to investigate the underlying reason for the back pain and 25 weakness of extremities. The MRI revealed an iliopsoas abscess due to methicillin-resistant 26 coagulase-negative staphylococci, supporting our diagnosis of TTP/TMA caused by infection. In 27 addition, the patient had discitis, potentially caused by the iliopsoas abscess. We evaluated her 28 microcirculation using TTDE, which showed impaired coronary flow reserve (CFR) in the left 29 anterior descending artery (LAD) (Fig. 3a), suggesting CMD caused by TTP/TMA. On day 10, a 30 cardiac MRI showed no evidence of an acute infarct area in the left ventricular myocardium (Fig. 31 4a and 4b). Plasma exchange was stopped based on the recovery of platelet count (21.3*10 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 /count; LDH 263 IU/L) on day 21, and corticosteroid therapy was tapered. The patient was 2 hemodynamically stable without symptoms of unconsciousness and recovered from TTP/TMA. 3 On day 22, coronary angiography was performed to exclude significant obstructive CAD. 4 Coronary angiography revealed no significant luminal stenosis in the LAD and left circumflex 5 artery (Supplementary fig. 2a), while the right coronary artery was small (the left dominance of 6 coronary arteries is shown in Supplementary fig. 2b). A follow-up assessment of the CFR on day 7 30 (Fig. 3b) demonstrated an improvement (CFR, 2.5), indicating recovery of the transient 8 impaired CMD as well as improvement in thrombocytopaenia. ADAMTS13 activity (day 4) was 9 preserved (34%, two weeks after the test), and the diagnosis was TMA. Oral prednisolone was 10 gradually reduced, and the iliopsoas abscess was treated with antibiotics for 3 months. The 11 patient was discharged without any symptom of heart or renal failure, and continued the 12 rehabilitation for several months because of a drop in her activities of daily living. 14 Discussion 15 CMD is the mechanism underlying myocardial infarction/injury with or without 16 epicardial obstructive coronary artery stenosis. TMA is a spectrum of life-threatening 17 syndromes, in which haemolytic anaemia and thrombocytopaenia are associated with multiple 1,2 18 organ damage. Complications include acute myocardial infarction/injury as the major cause of 19 death in patients with TMA. Cardiovascular system complications can be explained by 20 microvascular occlusions due to platelet aggregation. To the best of our knowledge, this is the 21 first report of CMD evaluation and its recovery in TMA. 22 ADAMTS13 deficiency causes TTP and is diagnosed when ADAMTS13 activity is 23 markedly reduced (<10%). This contributes to the formation of microthrombi and von 24 Willebrand factor multimers mediating platelet plugs. HUS caused by Shiga toxin-producing 25 Escherichia coli (STEC) is the most common cause of TMA associated with infectious diseases 26 (STEC-HUS). Complement-mediated TMA is atypical HUS (aHUS) and includes coagulation- 27 related TMA due to abnormalities in the thrombomodulin gene. Several underlying conditions 28 (autoimmune diseases, pregnancy, and haematopoietic stem cell transplantation) can also 29 contribute to secondary TMA. Disseminated intravascular coagulation should be considered in 30 the differential diagnosis of TMA; however, it is difficult to differentiate given the overlap at the 31 end stage of the disease. Samuel et al. showed that the initial normal ADAMTS13 activity may ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 fall substantially by 2 weeks. In our case ADAMTS13 activity was preserved despite the typical 2 TTP symptoms. This may be partially explained by the influence of FFP infusion on the 3 measurements for ADAMTS13 activity. 4 TMA is a pathological condition caused by endothelial cell damage in the small 5 terminal arteries and capillaries, as a result of complete or partial occlusion caused by platelet 6 and hyaline thrombi. This induces CMD and myocardial ischaemia, leading to myocardial 7 infarction (23.4%), heart failure (15.3%), and sudden cardiac death (7.2%). Approximately 60% 8 of patients with TTP have elevated cardiac troponin level; however, many patients are 9 asymptomatic. Cardiac troponin I level >0.25 μg/L is an independent factor of a three-fold 10 increased risk of death or refractoriness in these patients, indicating that this level of cardiac 11 troponin I can be a prognostic factor. 4,9 12 Persistent CMD can be observed via pathogenic and physiologic mechanisms. CMD 13 recovery is necessary for understanding the natural history of cardiac involvement caused by 14 myocardial infarction/injury in TMA. Moreover, persistent elevated cardiac troponin level could 15 be a useful marker for predicting short- and long-term mortality in various clinical settings, 16 including in patients with renal dysfunction. TMA with severe renal failure is often treated with 17 plasma exchange, which artificially reduces troponin level. CFR assessed by TTDE was found to 18 be associated with poorer CV outcomes in patients with chronic kidney disease, serving as an 19 alternative marker for predicting TMA outcomes. Although plasma exchange is the first-line 20 therapy recommended for patients with TTP, plasma exchange was not started immediately after 21 TTP diagnosis in our case. Some cases do not meet the diagnostic criteria for TTP despite the 22 presence of typical features, yet effectively respond to plasma exchange therapy. Similar to the 23 present case, these cases are considered analogous to TTP, and conventional plasma exchange 24 and supportive care using FFP could be useful. In addition to standard therapy including plasma 25 exchange and steroid therapy, pharmacological agents such as caplacizumab and rituximab have 26 been reported to be effective in patients with TTP accompanied by cardiac involvement. 27 Our case demonstrates the importance of identifying the recovery of the coronary 28 microvascular function, as it could be a predictive factor in TMA. One possible explanation for 29 the negative cardiac magnetic resonance (CMR) findings in our case is the relatively low 30 diagnostic accuracy of the late gadolinium enhancement in detecting myocardial 31 infarction/damage in patients with MINOCA. The European Society of Cardiology guideline ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 indicates that TTDE of the LAD, CMR, and PET may be considered for the non-invasive 2 assessment of CFR (class IIb) in patients with suspected coronary microvascular angina. 3 Although CFR assessment with TTDE is a cost-effective, non-invasive method utilised in daily 4 clinical practice, the serial measurements should be interpreted with caution given their limited 5 reproducibility. Non-invasive assessment of CMD with MRI or positron emission 6 tomography/CT was not available at our institution; however, it could be a useful diagnostic tool 7 for evaluating CMD. 9 Conclusions 10 In vivo evaluations of coronary microvascular function can provide mechanistic insights into the 11 cardiac involvement in TMA. Further studies are warranted to determine whether non-invasive 12 assessment of microvascular function enables disease progression predictions and provides 13 prognostic implications beyond cardiac troponin elevation in patients with TMA. 15 Statement of consent 16 The authors confirm that written consent for the submission and publication of this case report, 17 including images and associated text, has been obtained from the patient, in line with COPE 18 guidance. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 References 2 1. George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 3 2014;371:654–666. 4 2. Wahla AS, Ruiz J, Noureddine N, Upadhya B, Scane DC, Owen J. Myocardial infarction 5 in thrombotic thrombocytopenic purpura: a single-center experience and literature review. 6 Eur J Haematol 2008;81:311–316. 7 3. Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al. 2019 8 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. Eur 9 Heart J 2020;41:407–477. 10 4. Camici PG, d’Amati G, Rimoldi O. Coronary microvascular dysfunction: mechanisms and 11 functional assessment. Nat Rev Cardiol 2015;12:48–62. 12 5. Scully M, Hunt BJ, Benjamin S, Liesner R, Rose P, Peyvandi F, et al. Guidelines on the 13 diagnosis and management of thrombotic thrombocytopenic purpura and other thrombotic 14 microangiopathies. Br J Haematol 2012;158:323–335. 15 6. Samuel A, Garris R, Upadhyay S, Ghrewati M, Guragai N. An Atypical Presentation of 16 Thrombotic Thrombocytopenic Purpura With Concurrent Acute Coronary Syndrome and 17 Cerebrovascular Accident. Chest 2019;156:A1262. 18 7. Hawkins BM, Abu-Fadel M, Vesely SK, George JN. Clinical cardiac involvement in 19 thrombotic thrombocytopenic purpura: a systematic review. Transfusion 2008;48:382– 20 392. 21 8. Benhamou Y, Boelle P-Y, Baudin B, Ederhy S, Gras J, Galicier L, et al. Cardiac troponin- 22 I on diagnosis predicts early death and refractoriness in acquired thrombotic 23 thrombocytopenic purpura. Experience of the French Thrombotic Microangiopathies 24 Reference Center. J Thromb Haemost 2015;13:293–302. 25 9. Kubo T, Fukuda S, Hirata K, Shimada K, Maeda K, Komukai K, et al. Comparison of 26 coronary microcirculation in female nurses after day-time versus night-time shifts. Am J 27 Cardiol 2011;108:1665–1668. 28 10. Otsuka K, Nakanishi K, Shimada K, Nakamura H, Inanami H, Nishioka H, et al. 29 Associations of sensitive cardiac troponin-I with left ventricular morphology, function and 30 prognosis in end-stage renal disease patients with preserved ejection fraction. Heart 31 Vessels 2018;33:1334–1342. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 11. Nakanishi K, Fukuda S, Shimada K, Miyazaki C, Otsuka K, Kawarabayashi T, et al. 2 Prognostic value of coronary flow reserve on long-term cardiovascular outcomes in 3 patients with chronic kidney disease. Am J Cardiol 2013;112:928–932. 4 12. Lintingre PF, Nivet H, Clément-Guinaudeau S, Camaioni C, Sridi S, Corneloup O, et al. 5 High-Resolution Late Gadolinium Enhancement Magnetic Resonance for the Diagnosis of 6 Myocardial Infarction With Nonobstructed Coronary Arteries. JACC Cardiovasc Imaging 7 2020;13:1135–1148. 8 13. Rigo F, Richieri M, Pasanisi E, Cutaia V, Zanella C, Valentina PD, et al. Usefulness of 9 coronary flow reserve over regional wall motion when added to dual-imaging 10 dipyridamole echocardiography. Am J Cardiol 2003;91:269–273. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Figure legends 2 Figure 1. X-ray and electrocardiogram on admission. 3 Figure 1a. X-ray depicting bilateral congestion. 4 Figure 1b. Twelve-lead echocardiogram at admission showing ST depression in V5 and V6 5 leads, with sinus tachycardia and heart rate of 105 beats/min. 7 Figure 2. Purpura on both toes. 8 Day 2: Purpura on both toes. 10 Figure 3. Coronary flow reserve measured using transthoracic Doppler echocardiography 11 at baseline and follow-up. 12 The CFR value was calculated as the ratio of the baseline mean diastolic flow velocity at 13 baseline to the mean diastolic flow velocity at hyperaemia. 14 (a) Impaired coronary flow reserve in the left anterior descending artery at baseline, suggesting 15 coronary microvascular dysfunction caused by thrombotic microangiopathy (TMA). 16 (b) Serial assessment of coronary flow reserve on day 30 demonstrated an improvement. There 17 was no significant ST-T change on ECG during follow-up, whereas LV wall motion was 18 improved after intensive care, including management of heart failure. 20 Figure 4. CMR images. 21 4a and 4b. Late gadolinium enhancement with cardiac magnetic resonance (CMR) imaging 22 showed no acute infarct area in the myocardium of the left ventricle. Abnormal left ventricular 23 kinesis as well as ST-T change on ECG was improved at the time of CMR. CMR images 24 revealed pericardial effusion. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 2 Figure 1 3 165x93 mm ( x DPI) 6 Figure 2 7 165x93 mm ( x DPI) ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 2 Figure 3 3 165x93 mm ( x DPI) 6 Figure 4 7 165x93 mm ( x DPI) ACCEPTED MANUSCRIPT http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Heart Journal - Case Reports Oxford University Press

Evaluations of coronary microvascular dysfunction in a patient with thrombotic microangiopathy and cardiac troponin elevation: a case report

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Abstract

Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Evaluations of Coronary Microvascular Dysfunction in a Patient 2 with Thrombotic Microangiopathy and Cardiac Troponin 3 Elevation: A Case Report 1* 1 1,2 5 Kenichiro Otsuka, MD, PhD ; Yasushi Kono, MD, PhD ; Kumiko Hirata, MD, PhD 7 Department of Cardiovascular Medicine, Fujiikai Kashibaseiki Hospital, Kashiba, Japan, 8 Department of Medical Science, Osaka Educational University, Kashiwara, Osaka, Japan 9 https://orcid.org/0000-0001-6780-7034 11 Funding: none 12 Acknowledgement: none 13 Conflicts of interest: none 14 Author contributions: Y.K. prepared the manuscript draft. K.O. conceived study design and 15 prepared the manuscript draft. K.H. supervised the manuscript. 17 *Corresponding author 18 Kenichiro Otsuka 19 Department of Cardiovascular Medicine 20 Fujiikai Kashibaseiki Hospital 21 Address: 3300-3 Anamushi, Kashiba, Japan 22 Tel: +81-745-71-3113 23 Email: otsukakenichiro1@gmail.com © The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. 1 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 2 165x110 mm ( x DPI) 5 Learning Points 6  Thrombotic microangiopathy (TMA) can be life-threatening, and its underlying 7 mechanisms involve platelet aggregation and increased mechanical stress in the 8 microcirculation. 9  Coronary microvascular dysfunction (CMD) caused by TMA contributes to multiple 10 organ failure, myocardial infarction/injury, and sudden cardiac death. 11  Non-invasive assessment of coronary microvascular function and its recovery can 12 provide mechanistic insights into the cardiac involvement in TMA. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Timeline Admission Day 1 Treatment with bi-level positive airway pressure (BiPAP), carperitide, diuretics, and antibiotics in the intensive care unit. Blood culture and urine cultures were performed. Day 2 Transient neurologic deficits. Fresh frozen plasm infusion. Day 3 Treatment with steroid pulse therapy (1 g/day for 3 days), and plasma exchange. Day 5 BiPAP free, treatment with aspirin. Day 6 Prednisolone 40 mg/day. Day 7 TTDE revealed impaired coronary flow reserve (CFR = 1.7). No evidence of an acute infarct area on cardiac magnetic resonance imaging. Day 21 Plasma exchange free, prednisolone 30 mg, renal function improved, move out from high-care unit. Day 22 Invasive coronary angiography. Day 30 Follow-up TTDE demonstrated improved CFR of 2.5. Day 35 Prednisolone 20 mg/day (tapered by 5 mg/week). Day 50 Prednisolone 10 mg/day (tapered by 2.5 mg/2 weeks). Day 90 Antibiotics free, blood culture negative. Day 120 Discharged with prednisolone 5 mg/day after rehabilitation. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Abstract: 2 Background: Thrombotic microangiopathy (TMA) syndromes include thrombotic 3 thrombocytopenic purpura (TTP) and haemolytic uremic syndrome, and contribute to myocardial 4 infarction and multiple organ failure. Although coronary microvascular dysfunction (CMD) is 5 the key for understanding the pathophysiology of cardiac involvement in TMA, there is limited 6 knowledge on the recovery from CMD in patients with TMA. 7 Case summary: An 80-year-old woman was brought to the emergency department due to 8 worsening back pain, dyspnoea on exertion, jaundice, and fever. Although she had typical TTP 9 symptoms and elevated cardiac troponin level, ADAMTS13 activity was preserved (34%), 10 leading to the diagnosis of TMA with myocardial infarction. She underwent plasma exchange 11 and was administered aspirin and prednisolone. Magnetic resonance imaging revealed iliopsoas 12 abscess, which is a possible etiologic factor of sepsis-related TTP. She had impaired coronary 13 flow reserve (CFR) with angiographically nonobstructive epicardial coronary arteries. Improved 14 CFR was observed on follow-up, suggesting existence of transient CMD caused by TMA. After 15 treatment of the iliopsoas abscess with antibiotics for 3 months, she was discharged without any 16 adverse complications. 17 Discussion: CMD is an underlying mechanism of myocardial infarction, with or without 18 epicardial obstructive coronary artery stenosis. TMA is characterised by pathological lesions 19 caused by endothelial cell damage in small terminal arteries and capillaries, with complete or 20 partial occlusion caused by platelet and hyaline thrombi. CMD and its recovery are key for 21 understanding the natural history of cardiac involvement in TMA. In vivo evaluations of CMD 22 can provide mechanistic insights into the cardiac involvement in TMA. 24 Keywords: thrombotic microangiopathy, thrombotic thrombocytopenic purpura, coronary 25 microvascular dysfunction, cardiac troponin, myocardial infarction with nonobstructive coronary 26 arteries, case report ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Introduction 2 Thrombotic microangiopathy (TMA) is a spectrum of life-threatening syndromes, 3 including thrombotic thrombocytopenic purpura (TTP) and haemolytic uremic syndrome 4 (HUS). The mechanisms underlying TMA involve platelet aggregation and increased 5 mechanical stress in the microcirculation that contribute to multiple organ failure, including renal 1,2 6 and heart failure, myocardial infarction/injury, and sudden cardiac death. 7 Myocardial infarction/injury is defined by the presence of cardiac troponin elevation 8 caused by structural or functional obstruction of the coronary arteries. In a single centre study, 9 Wahla et al. demonstrated 15.3% of the patients diagnosed with TTP (n = 85) had myocardial 10 infarction. Furthermore, myocardial infarction of the nonobstructive coronary arteries 3,4 11 (MINOCA) can also cause cardiac troponin elevation. Although assessment of the coronary 12 microvascular function is important for understanding the pathophysiology of TMA, there are 13 limited reports on in vivo evaluations of coronary microvascular dysfunction (CMD) and its 14 recovery. Herein, we describe a case of cardiac troponin elevation with CMD associated with 15 TMA, demonstrating non-invasive assessment of the recovery of the coronary microvascular 16 function. 18 Case presentation 19 An 80-year-old woman presented to the emergency department with a 2-week history of 20 worsening back pain, a 5-days history of dyspnoea on exertion, and high temperature. 21 Approximately two weeks before admission she had an episode of back pain and high 22 temperature, and two days before admission she had transient unconsciousness and elevated 23 temperature (40°C). She was a passive smoker on oral antidiabetic medication, and had no 24 documented medical history of prior TTP or autoimmune disorder. On physical examination, she 25 was conscious, had dyspnoea without chest pain, a body temperature of 38.2°C, blood pressure 26 of 106/72 mmHg, pulse of 110 beats/min with 90% oxygen saturation (room air), and bilateral 27 rales; regular heart rhythm; Ⅱ/Ⅵ systolic murmur at apical; distension of the neck veins; 28 jaundice; and petechiae and purpura in her toes. A neurological examination revealed no focal 29 neurologic deficit. Laboratory tests (Table 1) revealed decreased platelet count of 13,000/μL and 30 estimated glomerular filtration rate of 22 ml/min/1.73 mm , increased level of total bilirubin of 31 7.3 mg/dl, increased level of lactate dehydrogenase (LDH) of 812 IU/L, and elevated levels of ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 brain natriuretic peptide and cardiac enzymes (411 IU/L creatine kinase [CK], 40 IU/L CK-MB, 2 and 19,966 pg/mL cardiac troponin I). Chest radiography revealed congestion (Fig. 1a), and a 3 12-lead electrocardiogram on admission showed ST depression in V5 and V6 leads with normal 4 sinus rhythm and a heart rate of 105 beats/min (Fig. 1b). Transthoracic Doppler 5 echocardiography (TTDE) revealed a preserved left ventricular ejection fraction (50%) with 6 hypokinesis of the inferior-posterior wall, suggesting non-ST-segment myocardial infarction. 7 Chest computed tomography (CT) examination revealed lung congestion but no signs of 8 infection. Brain magnetic resonance imaging (MRI) and CT showed no evidence of cerebral 9 haemorrhage (Supplementary Fig. 1a) or infarction (Supplementary Fig. 1b). 10 Considering the severe thrombocytopaenia the management of non-ST-elevation 11 myocardial infarction and heart failure was conservative, with non-invasive respiratory support 12 of the bi-level positive airway pressure, carperitide (0.025 μg/kg/ml), and diuretics (furosemide, 13 20 mg/day), in the intensive care unit. On day 2, the patient had transient neurologic deficits, 14 including 2/5 weakness in both arms, 2/5 weakness in both legs, dysarthria, and 15 unconsciousness. Given the presence of the classic pentad of TTP, including fever, 16 thrombocytopaenia, haemolytic anaemia, renal dysfunction, and neurologic deficit, the initial 17 diagnosis was TTP, and the patient was managed by a multidisciplinary team including 18 specialists from Cardiology, Haematology, Orthopaedics, and Neurology departments. After 19 administration of fresh frozen plasma (FFP) infusion, her platelet count decreased to 6,000/μL 20 with worsening leg purpura (Fig. 2). From day 3 onwards plasma exchange was performed 3 21 times/week. Steroid pulse therapy (1 g/day for 3 days) was administered, followed by high-dose 22 oral steroid therapy (prednisolone 40 mg/day). On day 5, oral aspirin (100 mg/day) was 23 administered, after recovery of her platelet count to >50,000/µL. 24 Spine MRI was performed to investigate the underlying reason for the back pain and 25 weakness of extremities. The MRI revealed an iliopsoas abscess due to methicillin-resistant 26 coagulase-negative staphylococci, supporting our diagnosis of TTP/TMA caused by infection. In 27 addition, the patient had discitis, potentially caused by the iliopsoas abscess. We evaluated her 28 microcirculation using TTDE, which showed impaired coronary flow reserve (CFR) in the left 29 anterior descending artery (LAD) (Fig. 3a), suggesting CMD caused by TTP/TMA. On day 10, a 30 cardiac MRI showed no evidence of an acute infarct area in the left ventricular myocardium (Fig. 31 4a and 4b). Plasma exchange was stopped based on the recovery of platelet count (21.3*10 ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 /count; LDH 263 IU/L) on day 21, and corticosteroid therapy was tapered. The patient was 2 hemodynamically stable without symptoms of unconsciousness and recovered from TTP/TMA. 3 On day 22, coronary angiography was performed to exclude significant obstructive CAD. 4 Coronary angiography revealed no significant luminal stenosis in the LAD and left circumflex 5 artery (Supplementary fig. 2a), while the right coronary artery was small (the left dominance of 6 coronary arteries is shown in Supplementary fig. 2b). A follow-up assessment of the CFR on day 7 30 (Fig. 3b) demonstrated an improvement (CFR, 2.5), indicating recovery of the transient 8 impaired CMD as well as improvement in thrombocytopaenia. ADAMTS13 activity (day 4) was 9 preserved (34%, two weeks after the test), and the diagnosis was TMA. Oral prednisolone was 10 gradually reduced, and the iliopsoas abscess was treated with antibiotics for 3 months. The 11 patient was discharged without any symptom of heart or renal failure, and continued the 12 rehabilitation for several months because of a drop in her activities of daily living. 14 Discussion 15 CMD is the mechanism underlying myocardial infarction/injury with or without 16 epicardial obstructive coronary artery stenosis. TMA is a spectrum of life-threatening 17 syndromes, in which haemolytic anaemia and thrombocytopaenia are associated with multiple 1,2 18 organ damage. Complications include acute myocardial infarction/injury as the major cause of 19 death in patients with TMA. Cardiovascular system complications can be explained by 20 microvascular occlusions due to platelet aggregation. To the best of our knowledge, this is the 21 first report of CMD evaluation and its recovery in TMA. 22 ADAMTS13 deficiency causes TTP and is diagnosed when ADAMTS13 activity is 23 markedly reduced (<10%). This contributes to the formation of microthrombi and von 24 Willebrand factor multimers mediating platelet plugs. HUS caused by Shiga toxin-producing 25 Escherichia coli (STEC) is the most common cause of TMA associated with infectious diseases 26 (STEC-HUS). Complement-mediated TMA is atypical HUS (aHUS) and includes coagulation- 27 related TMA due to abnormalities in the thrombomodulin gene. Several underlying conditions 28 (autoimmune diseases, pregnancy, and haematopoietic stem cell transplantation) can also 29 contribute to secondary TMA. Disseminated intravascular coagulation should be considered in 30 the differential diagnosis of TMA; however, it is difficult to differentiate given the overlap at the 31 end stage of the disease. Samuel et al. showed that the initial normal ADAMTS13 activity may ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 fall substantially by 2 weeks. In our case ADAMTS13 activity was preserved despite the typical 2 TTP symptoms. This may be partially explained by the influence of FFP infusion on the 3 measurements for ADAMTS13 activity. 4 TMA is a pathological condition caused by endothelial cell damage in the small 5 terminal arteries and capillaries, as a result of complete or partial occlusion caused by platelet 6 and hyaline thrombi. This induces CMD and myocardial ischaemia, leading to myocardial 7 infarction (23.4%), heart failure (15.3%), and sudden cardiac death (7.2%). Approximately 60% 8 of patients with TTP have elevated cardiac troponin level; however, many patients are 9 asymptomatic. Cardiac troponin I level >0.25 μg/L is an independent factor of a three-fold 10 increased risk of death or refractoriness in these patients, indicating that this level of cardiac 11 troponin I can be a prognostic factor. 4,9 12 Persistent CMD can be observed via pathogenic and physiologic mechanisms. CMD 13 recovery is necessary for understanding the natural history of cardiac involvement caused by 14 myocardial infarction/injury in TMA. Moreover, persistent elevated cardiac troponin level could 15 be a useful marker for predicting short- and long-term mortality in various clinical settings, 16 including in patients with renal dysfunction. TMA with severe renal failure is often treated with 17 plasma exchange, which artificially reduces troponin level. CFR assessed by TTDE was found to 18 be associated with poorer CV outcomes in patients with chronic kidney disease, serving as an 19 alternative marker for predicting TMA outcomes. Although plasma exchange is the first-line 20 therapy recommended for patients with TTP, plasma exchange was not started immediately after 21 TTP diagnosis in our case. Some cases do not meet the diagnostic criteria for TTP despite the 22 presence of typical features, yet effectively respond to plasma exchange therapy. Similar to the 23 present case, these cases are considered analogous to TTP, and conventional plasma exchange 24 and supportive care using FFP could be useful. In addition to standard therapy including plasma 25 exchange and steroid therapy, pharmacological agents such as caplacizumab and rituximab have 26 been reported to be effective in patients with TTP accompanied by cardiac involvement. 27 Our case demonstrates the importance of identifying the recovery of the coronary 28 microvascular function, as it could be a predictive factor in TMA. One possible explanation for 29 the negative cardiac magnetic resonance (CMR) findings in our case is the relatively low 30 diagnostic accuracy of the late gadolinium enhancement in detecting myocardial 31 infarction/damage in patients with MINOCA. The European Society of Cardiology guideline ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 indicates that TTDE of the LAD, CMR, and PET may be considered for the non-invasive 2 assessment of CFR (class IIb) in patients with suspected coronary microvascular angina. 3 Although CFR assessment with TTDE is a cost-effective, non-invasive method utilised in daily 4 clinical practice, the serial measurements should be interpreted with caution given their limited 5 reproducibility. Non-invasive assessment of CMD with MRI or positron emission 6 tomography/CT was not available at our institution; however, it could be a useful diagnostic tool 7 for evaluating CMD. 9 Conclusions 10 In vivo evaluations of coronary microvascular function can provide mechanistic insights into the 11 cardiac involvement in TMA. Further studies are warranted to determine whether non-invasive 12 assessment of microvascular function enables disease progression predictions and provides 13 prognostic implications beyond cardiac troponin elevation in patients with TMA. 15 Statement of consent 16 The authors confirm that written consent for the submission and publication of this case report, 17 including images and associated text, has been obtained from the patient, in line with COPE 18 guidance. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 References 2 1. George JN, Nester CM. 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Rigo F, Richieri M, Pasanisi E, Cutaia V, Zanella C, Valentina PD, et al. Usefulness of 9 coronary flow reserve over regional wall motion when added to dual-imaging 10 dipyridamole echocardiography. Am J Cardiol 2003;91:269–273. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 1 Figure legends 2 Figure 1. X-ray and electrocardiogram on admission. 3 Figure 1a. X-ray depicting bilateral congestion. 4 Figure 1b. Twelve-lead echocardiogram at admission showing ST depression in V5 and V6 5 leads, with sinus tachycardia and heart rate of 105 beats/min. 7 Figure 2. Purpura on both toes. 8 Day 2: Purpura on both toes. 10 Figure 3. Coronary flow reserve measured using transthoracic Doppler echocardiography 11 at baseline and follow-up. 12 The CFR value was calculated as the ratio of the baseline mean diastolic flow velocity at 13 baseline to the mean diastolic flow velocity at hyperaemia. 14 (a) Impaired coronary flow reserve in the left anterior descending artery at baseline, suggesting 15 coronary microvascular dysfunction caused by thrombotic microangiopathy (TMA). 16 (b) Serial assessment of coronary flow reserve on day 30 demonstrated an improvement. There 17 was no significant ST-T change on ECG during follow-up, whereas LV wall motion was 18 improved after intensive care, including management of heart failure. 20 Figure 4. CMR images. 21 4a and 4b. Late gadolinium enhancement with cardiac magnetic resonance (CMR) imaging 22 showed no acute infarct area in the myocardium of the left ventricle. Abnormal left ventricular 23 kinesis as well as ST-T change on ECG was improved at the time of CMR. CMR images 24 revealed pericardial effusion. ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 2 Figure 1 3 165x93 mm ( x DPI) 6 Figure 2 7 165x93 mm ( x DPI) ACCEPTED MANUSCRIPT Downloaded from https://academic.oup.com/ehjcr/advance-article/doi/10.1093/ehjcr/ytac318/6651599 by DeepDyve user on 02 August 2022 2 Figure 3 3 165x93 mm ( x DPI) 6 Figure 4 7 165x93 mm ( x DPI) ACCEPTED MANUSCRIPT

Journal

European Heart Journal - Case Reports – Oxford University Press

Published: Jul 29, 2022

Keywords: Thrombotic microangiopathy; Thrombotic thrombocytopenic purpura; Coronary microvascular dysfunction; Cardiac troponin; Myocardial infarction with non-obstructive coronary arteries; Case report

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