Elevation Acute Coronary Syndrome in Patients
with Mechanical Prosthetic Heart Valves
(from the TROIA-ACS Trial)
D1X XMahmut Yesin,
D2X XMD
a,*,
D3X XS€uleyman Karakoyun,
D4X XMD
b,
D5X XMacit Kal¸cık,
D6X XMD
c,
D7X XMustafa Ozan G€ursoy,
D8X XMD
d,
D9X XSabahattin G€und€uz,
D10X XMD
e,
D11X XMehmet Ali Astarcıoglu,
D12X XMD
f,
D13X XEmrah Bayam,
D14X XMD
e,
D15X XSinan Cer¸sit,
D16X XMD
e,
D17X XAhmet G€uner,
D18X XMD
e, and
D19X XMehmet €Ozkan,
D20X XMD
e,gCoronary thromboembolism (CE) is a rare cause of prosthetic valve derived complica-tions. This study investigates the diagnosis and treatment strategies for non-ST elevation acute coronary syndrome (NSTEACS) in patients with prosthetic heart valves. Forty-eight NSTEACS patients with prosthetic heart valves (mitral:27; aortic:14; mitral+aortic:7) were included in this study. All patients underwent transthoracic and transesophageal echocardiographic examination and coronary angiography. Normal coronary angio-graphic findings, or visible trombus in one of the coronary arteries, international normal-ized ratio<2, concomitant prosthetic valve thrombosis (PVT) and absence of multivessel atherosclerotic disease favored CE rather than atherothrombosis. Thrombolytic therapy (TT) with low-dose slow-infusion of tissue type plasminogen activator was used in patients with suspected CE and/or PVT. Coronary angiography demonstrated normal coronary arteries in 26 patients, CE in 16 patients and coronary atherosclerosis in 6 patients. Trans-esophageal echocardiography revealed obstructive PVT in 9 and nonobstructive PVT in 28 patients whereas 11 patients had normally functioning prostheses. TT was adminis-tered to 24 patients with PVT and/or CE. In these patients, TT was successful in 19 patients, partially successful in 4 patients and failed in 1 patient. In conclusion, NSTEACS in patients with prosthetic heart valves is more likely to be associated with PVT derived CE rather than atherosclerosis. TT with low-dose slow infusion of type plasminogen acti-vator has proved its efficacy and safety in patients with CE and/or PVT. © 2018 Elsevier Inc. All rights reserved. (Am J Cardiol 2018;122:638 644)
Non-ST elevation acute coronary syndrome (NSTEACS) is a lethal condition of ischemic heart disease. The patho-physiology of NSTEACS most commonly includes disrup-tion of an atherosclerotic coronary plaque; activadisrup-tion of the coagulation cascade; and platelet activation, adhesion, and aggregation.1 Myocardial infarction may also occur in the absence of obstructive coronary artery disease on angiogra-phy which has been defined as ‘myocardial infarction with nonobstructive coronary arteries’ (MINOCA). There are disparate aetiologies causing MINOCA and coronary embolism is one of them.2NSTEACS may also be associ-ated with coronary embolism.3 7The predisposing factors for coronary embolism include infectious/noninfectious
endocarditis, arrhythmias, prosthetic heart valve, aortic thrombus, coronary artery disease, paradoxical embolism, heart valve surgery, dilated cardiomyopathy, and cardiac tumors such as myxoma and papillary fibroelastoma and pulmonary vein thrombosis.8 12 Prosthetic valve thrombo-sis (PVT) is a serious complication with high mortality and morbidity.13 Recent studies showed that thrombolytic therapy (TT) has become an important treatment option in patients with PVT.14 18 PVT derived coronary embolism is an important cause of NSTEACS in patients with pros-thetic heart valves.3 6The majority of patients who have prosthetic heart valve and present with ACS suffer NSTEACS rather than ST elevation acute coronary syn-drome (STEACS).19 Treatment options include coronary thrombectomy, percutaneous coronary intervention (PCI) with or without stenting, systemic or intracoronary TT, redo surgery, and conservative management with anticoag-ulant therapy. We aimed to evaluate the management of NSTEACS in patients with prosthetic heart valves in this largest study reported to date.
Methods
Between January 2009 and January 2017, 48 NSTEACS patients with prosthetic heart valves were recruited to this prospective and observational study. Patients with
a
Kars Harakani State Hospital, Department of Cardiology, Kars, Turkey; bKafkas University Medical School, Department of Cardiology, Kars, Turkey; cHitit University, Faculty of Medicine, Department of Cardiology, ¸Corum, Turkey; dGaziemir State Hospital, Department of Cardiology, _Izmir, Turkey; eKosuyolu Kartal Heart Training and
Research Hospital, Department of Cardiology, _Istanbul, Turkey; fEvliya
Celebi Training and Research Hospital, Department of Cardiology, K€utahya, Turkey; andgArdahan University, Division of Health Sciences,
Ardahan, Turkey. Manuscript received January 8, 2018; revised manuscript received and accepted April 19, 2018.
See page 643 for disclosure information.
*Corresponding author: Tel: (90) 5324726596; fax: (90) 474 2125671. E-mail address:mahmutyesin@yahoo.com(M. Yesin).
0002-9149/© 2018 Elsevier Inc. All rights reserved. www.ajconline.org
STEACS, haemodynamic instability or cardiogenic shock, recurrent or ongoing chest pain refractory to medical treat-ment, life-threatening arrhythmias or cardiac arrest, mechanical complications of myocardial infarction, acute heart failure and recurrent dynamic ST-T wave changes, intracranial neoplasm or cerebrovascular disease, history of cranial trauma or transient ischemic attack within 3 months, history of hemorrhagic stroke, active bleeding, and aortic dissection were excluded from the study.
NSTEACS was defined according to clinical symptoms of ischemia, electrocardiographic changes, and cardiac bio-markers. The patient demographics, elapsed time since valve surgery, type of the prosthetic valve, type of PVT, the coronary arteries involved, rhythm disorders, New York Heart Association class, anticoagulation status on hospital admission, risk factors for coronary artery disease, and lab-oratory data were prospectively entered into a database. All participants provided written informed consent for partici-pation in the study, which was approved by the institutional ethics committee.
All patients underwent transthoracic (TTE) and two-dimensional (2D) and real-time three-two-dimensional (RT-3D) transesophageal echocardiographic (TEE) examination. The TEE studies were performed using the X7-2t trans-ducer on an iE33 ultrasound machine (Philips Medical Systems, Andover, Massachusetts). Prostethic valve obstruction was defined on the basis of Doppler echocardio-graphic measurements (peak velocity, mean gradient, effec-tive orifice area, velocity ratio, and acceleration time, as appropriate).20 Thrombus was recognized as a homoge-nous, mobile, or fixed mass with similar echo density to the myocardium located at the valve occluder and/or valve struts and was visualized in all patients with PVT using echocardiography.21
All coronary angiography and primary PCI proce-dures were performed using Siemens Angiocore Machine (Germany) by experienced interventional cardi-ologists with standard methods through femoral or radial access to all patients within 24 hours after admission. After the assessment of the coronary anatomy and
culprit lesion, balloon predilatation, and/or thrombec-tomy (Figure 1) or coronary stent implantation was applied whenever necessary.
Fluoroscopic examination in the characteristic “side view-tilting disc” projection was performed to evaluate leaflet mobility.20Patients with aortic prostheses initially underwent TEE examination before coronary angiography to prevent catheter-related thromboembolism.4,5,22 Angiographic and hemodynamic data were analyzed by 2 different experienced interventional cardiologists. The criteria that favored coro-nary embolism rather than atherothrombosis included normal coronary angiographic findings, international normalized ratio less than 2, intraluminal staining, ovoid/spherical filling defect, presence of PVT, and visible coronary trombus with or without distal perfusion and absence of 2 to 3 vessel ath-erosclerotic disease (Figure 2; Videos 1 and 2).
Since the patients with STEACS and situations that require urgent coronary intervention in NSTEACS were excluded, the standard fast TT protocol for myocardial infarction was not performed in this study. Based on the previous studies that report the safety and effectiveness of low dose slow infusion TT protocol, 6 hours infusion of 25 mg tissue type plasminogen activator (t-PA) without a bolus (repeat once after 24 hours, up to 6 times if needed, maximum total dose of 150 mg) was used in patients with documented coronary embolism and/or PVT.3,13,14,16 Anticoagulation with intravenous unfractionated heparin was withheld during t-PA infusion due to increased risk of bleeding. Heparin 50 to 70 units/kg bolus and 16 IU/kg per hour (up to 1000 IU/h) infusion with a target activated par-tial thromboplastin time (aPTT) between 1.5 and 2.5 times the control was started immediately after t-PA infusion. If repeated TT was needed, heparin was withheld again until aPTT was less than 50 seconds. All patients underwent TTE and TEE examination within an hour after TT sessions.
In the absence of fatal and nonfatal major adverse events, (a) complete lysis of the coronary thrombus and res-toration of TIMI III coronary flow, (b) Doppler documenta-tion of the complete improvement in valve hemodynamics and complete normalization of leaflet mobility, (c) reduc-tion in major diameter and/or area of the thrombus by 75%, and (d) symptomatic improvement were considered as the major criteria for TT success in patients with obstructive PVT. Complete success was defined when all 4 criteria were met, and partial success as less than 4. For patients with nonobstructive PVT, the only criterion for TT success was the complete lysis of the mobile component of the thrombus with overall reduction in thrombus burden not being less than 75%. Partial success was defined as 50% and 75% reduction in thrombus area and/or length14 16,20 (Figure 3; Videos 3 and 4).
Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 19.0. (IBM Corp. Armonk, New York). Descriptive statistics are reported as mean § standard deviation for continuous variables with normal distribution or median (Twenty-fifth to Seventy-fifth per-centiles) values for continuous variables without normal distribution and as frequency with percentages for the cate-gorical variables. The Kolmogorov Smirnov test was used to test the normality of distribution of continuous variables. Categorical variables were compared with the use of
chi-Figure 1. The thrombus aspiration with coronary thrombus aspiration cath-eter yielded a worm-like thrombus material which ws histopathologically confirmed as thrombus.
Figure 2. Coronary angiography demonstrated coronary thrombus in the left anterior descending (A), circumflex (B), and right coronary arteries (C) causing cut off pattern of coronary blood flow in a patient with the diagnosis of coronary embolism (A) and complete lysis of the thrombus after thrombolytic therapy with low-dose slow-infusion of tissue-type plasminogen activator (A’, B’, C’ respectively).
The American Journal of Cardiology ( www.ajconlin e.org )
square test. Significance level was accepted as p<0.05 in all statistical analyses.
Results
Forty-eight NSTEACS patients (median age: 55 [47 to 60], female: 39.6%) with prosthetic heart valves (mitral:27; aor-tic:14; mitral+aortic:7) were enrolled in this study. The clini-cal characteristics of the patients are listed in Table 1. On admission atrial fibrillation was present in 19 (39.6%) patients (11/26 in patients with normal coronary arteries, 5/16 in patients with coronary embolism, and 3/6 in patients with atherosclerotic coronary involvement). The median inter-national normalized ratio on admission was 1.65 (1.3 to 2.1).
TTE, 2D and real-time three-dimensional TEE demon-strated PVT (Figure 3) in 37 patients including 21 (43.8%) mitral, 12 (25%) aortic and 4 (8.3%) aortic+mitral valves. The remaining 11 (22.9%) patients had normally function-ing prosthetic valves without thrombosis. Twenty five (52.1%) patients had nonobstructive thrombus (mitral:19; aortic:6) and 8 (16.7%) patients had obstructive thrombus (mitral:2; aortic:6). One (2.1%) patient had obstructive
aortic valve thrombosis and nonobstructive mitral valve thrombosis whereas 3 (6.3%) patients had nonobstructive thrombi on both mitral and aortic valves.
Coronary angiographic evaluation of the patients who were admitted with NSTEACS demonstrated normal coro-nary arteries in 26 patients and corocoro-nary lesions in 22 patients. In 16 of 22 patients with coronary lesions, coronary embolism was diagnosed on the basis of visible coronary thrombus and/or cut-off pattern of coronary blood flow (Figure 2A, B, and C). In the remaining 6 patients the ACS was attributed to coronary atherosclerosis. In the group with coronary embolism, 9 patients had nonobstructive PVT (aort:4; mitral:5), 4 patients had obstructive PVT (aort:3; mitral:1), 1 patient had nonobstructive PVT in both aortic and mitral prostheses, and 2 patients had thrombus free nor-mal functioning prosthetic valves. TT was performed in 14 patients with the diagnosis of coronary embolism due to prosthetic valve and/or coronary embolism. Due to partial coronary success in 2 patients after TT, percutaneous throm-bus aspiration was performed. TT was successful in 11 (78.5%) patients (Figure 2A’, B’, and C’) and partial suc-cess was achieved in 3 (21.5%) patients. The median tPA dose administered was 50 (25 to 50) mg.
Figure 3. Two-dimensional and real-time three-dimensional transesophageal echocardiography demonstrated an obstructive thrombus on mitral prosthetic valve in a patient who admitted with non-ST elevation acute coronary syndrome (A and B) and complete lysis of the thrombus after thrombolytic therapy with low-dose slow-infusion of tissue-type plasminogen activator (C and D).
In the group with atherosclerotic coronary artery disease, 3 of 6 patients had nonobstructive PVT and the remaining 3 patients had thrombus-free normally functioning prosthetic valves. PCI was performed in 2 patients with severe athero-sclerotic lesions. One patient was referred for coronary artery bypass graft surgery due to complex multivessel dis-ease. The remaining 3 patients were followed up with anti-ischemic medical therapy.
In 26 patients with normal coronary arteries, 13 (50%) patients had nonobstructive PVT, 4 (15.4%) patients had obstructive PVT, 1 (3.8%) patient had obstructive PVT in aortic valve and nonobstructive PVT in mitral valve, 2 (7.7%) patient had non-obstructive PVT in both aortic and mitral valves, and 6 (23%) patients had thrombus-free normally functioning prosthetic valves. In this group, 16 patients were followed up with medical therapy and TT was administered in 10 patients for PVT. TT was successful in 8 (80%) patients and partial success was achieved in 1 (10%) patient (Figure 3). TT with up to 150 mg tPA infusion failed in 1(10%) patient with obstructive mitral PVT who was then referred for redo valve surgery. The median tPA dose admin-istered was 50 (25 to 62.5) mg in this group.
In patients with coronary embolism, left anterior descend-ing coronary artery was involved in 12 (75%) patients, cir-cumflex coronary artery in 3 (18.8%) patients, and right coronary artery in 1 (6.2%) patient. Left coronary system involvement accounted majority (93.8%) of the patients with coronary embolism. In the atherosclerotic coronary artery dis-ease group, 2 patients had left anterior descending coronary artery lesion, 1 patient had circumflex coronary artery lesion, 1 patient had right coronary artery lesion, 1 patient who was referred to CABG surgery had multivessel disease, and 1 patient had saphenous graft lesion.
A total of 24 patients received TT for PVT and/or coro-nary embolism. In these patients 13 (54.2%) had nonob-structive PVT, 7 (29.2%) had obnonob-structive PVT, 1 (4.2%) patient had obstructive PVT in aortic valve and tive PVT in mitral valve, 2 (8.2%) patient had nonobstruc-tive PVT in both aortic and mitral valves, and 1 (4.2%) had thrombus free normally functioning prosthetic valve. In 13 patients PVT accompanied to coronary embolism, 1 patient had only coronary embolism without PVT and 10 patients had only PVT without coronary embolism. In these 24 patients, TT was successful in 19 (79.2%) patients, partially successful in 4 (16.7%) patients and failed in 1(4.2%) patient. There was no major complication (0%), no death (0%), and only 1 (4.2%) minor complication (minor bleed-ing not requirbleed-ing transfusion).
Of 16 patients with coronary embolism, 14 received TT. The success rate was 85.7% (12/14) in these patients. The remaining 2 patients were treated with PCI after partially successful TT. Similarly, 23 patients who had the diagnosis of PVT received TT. Complete success for PVT was achieved in 21 (91.4%) patients and partial success in 1 (4.3%) patient. TT failed in 1 (4.3%) patient with obstruc-tive PVT who was referred for redo valve surgery.
Discussion
The main results of present study is that, coronary embo-lism, as compared with atherosclerotic coronary artery
Table 1
Clinical and laboratory characteristics of patients (n = 48) Variable Age (years) 55 (47-60) Male 29 (60.4%) Hypertension 12 (25%) Diabetes Mellitus 10 (20.8%) Smoking 12 (25%) Hyperlipidemia 5 (10.4%)
Family history of coronary artery disease 8 (16.6%) Native valve pathology
Degenerative 15 (31%)
Rheumatic 23 (48%)
Unknown 10 (21%)
Prosthetic valve position
Mitral 27 (56.3%)
Aortic 14 (29.2%)
Mitral + aortic 7 (14.6%)
Prosthetic valve thrombosis 37 (75.1%)
Mitral 21 (43.8%)
Aortic 12 (25%)
Mitral + aortic 4 (8.3%)
Spontaneous echo contrast 5 (10.4%) Type of prosthetic valve thrombosis
Obstructive (% of total thrombosed valves) 9 (21.9%) Non-Obstructive (% of total thrombosed valves) 32 (78.1%) Time from surgery to non ST elevation acute
coronary syndrome (months)
30 (12-60) Atrial fibrillation on admission 19 (39.6%) INR:International normalised ratio on admission 1.65 (1.3-2.1) NewYork Heart Association class I-II 36 (75.1%) NewYork Heart Association class III-IV 12 (24.9%)
Troponin-I (ng/mL) 5.05 (1.8-13.6)
Creatine kinase (IU/L) 261.5 (150-575.6) Creatine kinase myocardial band (IU/L) 38.5 (27.2-54.2) White blood cell (£109cells/L) 10.1§3.6
Hemoglobin (g/dL) 12.6§2.4
Platelet (£103cells/mL) 282 (216-340)
Urea (mg/dL) 34 (28.2-51.5)
Kreatinin (mg/dL) 1 (0.86-1.2)
Uric acid (mg/dL) 5.3 (4.7-6.1)
Lactate dehydrogenase (IU/L) 576 (342-880) Brain natriuretic peptide (pg/mL) 242 (117-492)
D-Dimer (ng/mL) 0.8 (0.37-1.38)
Erythrocyte sedimentation rate (mm/h) 36 (20.7-53.2) C-reactive protein (mg/L) 1.6 (0.9-3.5) Left ventricular ejection fraction (%) 50 (45-60) High density lipoprotein (mg/dL) 37.4 (32.3-42) Low density lipoprotein (mg/dL) 125 (96.5-148.7) Drugs on admission Warfarin 48 (100%) Aspirin 9 (19%) Digoxin 4 (10%) Beta-bockers 21 (43%) Angiotensin-converting-enzyme inhibitor/ Angiotensin receptor blocker
22 (46%)
Lipid lowering therapy 13 (27%)
(Continuous variables with normal distribution were expessed as mean § standard deviation and continuous variables without normal distribution were expressed as median (Twenty-fifth to Seventy-fifth percentiles), cate-gorical variables were expressed as frequencies (percentages)).
disease, is more commonly encountered in patients with pros-thetic heart valves presenting with NSTEMI with or without documented PVT. Moreover, TT with low-dose and slow-infusion of tPA seems to have a remarkable potential of lysis for both prosthetic and coronary thrombi. Indeed, interven-tional and surgical procedures are rarely required in the con-text of NSTEACS and prosthetic valve co-occurence.
This study included 48 patients who had prosthetic heart valves and were admitted with NSTEACS. Coronary angi-ography demonstrated normal coronary arteries in 26 (54.2%) patients, coronary embolism in 16 (33.3%) patients and coronary atherosclerosis in 6 (12.5%) patients. TEE revealed obstructive (n:9) or nonobstructive (n:28) PVT in 37 patients and normally functioning prostheses in 11 patients. TT with low-dose slow-infusion of tPA, which has been recently reported to be safe and successful for the treatment of PVT,18 21 was administered to 24 patients with PVT and/or coronary embolism. In these patients, TT was successful in 19 (79.2%) patients, partially successful in 4 (16.7%) patients and failed in 1(4.2%) patient without any fatal or nonfatal major complication. The complete success rates of TT for the coronary embolisms and PVTs were 85.7% and 91.4%, respectively.
ACS is a rare but life-threatening complication of pros-thetic heart valves. The infarct size caused by coronary artery embolism is strongly associated with the diameter of the occluded coronary artery.23Coronary embolism is most commonly observed in the left coronary system (63.6%) due to anatomic morphologic of aortic annulus and physio-logical processes in the aortic root.24In the present study, left coronary system was involved in majority (93.8%) of the patients with coronary embolism. Most of these coro-nary emboli were localized in the distal corocoro-nary bed or rarely on the proximal bifurcation areas.
Coronary embolism should be considered in the differ-ential diagnosis when patients with dilated cardiomyopathy, atrial fibrillation, heart failure with low ejection fraction, hypercoagulopaty, infective endocarditis, intracardiac shunts, and prosthetic valves admit with new-onset angina pectoris and MINOCA.25 27Of 19 patients with AF in the present study, 3 had atherosclerotic heart disease and 16 had coronary embolism or normal coronary arteries, indi-cating that patients those with AF may have increased risk for coronary embolism and MINOCA. The main diagnostic tool is clinical suspicion and the other modalities (coronary angiography, 2D and 3D TEE and cardiac markers) play complementary role in the diagnosis of coronary embolism. Especially patients with aortic prostheses should undergo initial TEE examination before coronary angiography to prevent catheter-related thromboembolism.4,5,28
There is lacking data regarding the management of patients who suffered from PVT derived NSTEACS. Sev-eral investigators suggested thrombus aspiration26 while some others preferred PCI and coronary stent implantation which may be associated with distal embolisation of the coronary thrombus and no re-flow phenomenon.29 Hence, coronary stenting is not frequently suggested for the treat-ment of coronary embolism which is associated with nor-mal coronary arteries rather than atherosclerosis. In contrast, TT is contraindicated in the presence of infective endocarditis and vegetations.
In this study 14 patients with coronary embolism received TT with low-dose slow-infusion of tPA (25 mg per 6 hours) protocol which was previously proved to be safe and successful in several studies.14 16 Two patients were followed up with anti-ischemic medical therapy since coronary embolism was tiny and distally localized. TT was successfully performed for both PVT and coronary embo-lism in 11 patients. However in 2 patients, PCI was admin-istered due to ongoing angina and heart failure symptoms, so TT was partially successful in these patients although complete lysis of PVT was achieved.
Of 48 patients who were diagnosed with NSTEACS, 26 had normal coronary arteries with or without concomitant PVT, suggesting possible spontaneous lysis of coronary thrombus, as reported previously.30 Therefore, coronary embolism may be, indeed, more common in prosthetic heart valve patients who admit with NSTEACS.
This study has several limitations. Although being rela-tively large, it is a single-center prospective study with a relatively limited and selected patient population who had prosthetic heart valves and NSTEACS on admission. Intra-vascular ultrasound or optical coherence tomographyAˆ was not used for identification of coronary thromboembolism. Furthermore, provocation tests were not performed to diag-nose any coronary vasospasm.
In conclusion, patients with prosthetic heart valves and NSTEACS are a rare subgroup and PVT derived coronary embolism is one of the causes of MINOCA in these patients. In this study with the largest patient population reported to date, TT with low-dose slow infusion of tPA has proved its efficacy and safety in patients with coronary embolism and/or PVT.
Contributorship
All of the investigators contributed planning, conduct, and reporting of the work. All investigators had full access to all data in the study and take responsibility for the integ-rity of the data and the accuracy of the data analysis.
Disclosures
The investigators have no conflicts of interest to disclose.
Supplementary Data
Supplementary data associated with this article can be found, in the online version, athttps://doi.org/10.1016/j.amj card.2018.04.045.
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