Bioresorbable Vascular Scaffold Thrombosis in an All-Comer Patient Population: Single-Center Experience

Abstract: Experience with bioresorbable vascular scaffolds (BVSs) outside clinical trials is scarce, and data from “real-world” use are needed. In particular, there are few data on scaffold thrombosis (ST). We report our experience with ST in our all-comer BVS population (n = 339) and review the literature on the topic. Four cases (1.2%) of early definite ST were identified. Multiple risk factors were present in all 4 cases. Optical coherence tomography ruled out mechanical causes of ST in 2 cases, whereas scaffold underexpansion was observed in 1 case. Twelve BVS series have been published to date. Total sample size includes 1393 patients, with 13 cases of definite ST (0.9%), which is similar to long-term second-generation drug-eluting stent thrombosis rate (1.0%). Eleven of these cases were early ST (8 during the first week). Six of these 11 cases occurred in patients who received a BVS in the setting of an acute coronary syndrome (ACS). It can be speculated that the prothrombotic milieu of ACS, coupled with the unfavorable peristrut rheology of BVSs, might promote ST early after implantation, particularly if other concomitant risk factors are present. 

J INVASIVE CARDIOL 2015;27(2):85-92

Key words: bioresorbable vascular scaffold, scaffold thrombosis, stent thrombosis, percutaneous coronary intervention, acute coronary syndrome

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Bioresorbable vascular scaffolds (BVSs) may represent the future in the percutaneous treatment of coronary artery disease (CAD), since they provide temporary scaffolding and then disappear within 2 years of implantation, once plaque mechanical stabilization and healing have occurred.^1,2 This property allows restoration of vasomotion, mechano-transduction and adaptive shear stress of the coronary arteries, and late luminal gain.³ Moreover, the restoration of a functional endothelium and the absence of any residual foreign material could potentially reduce the risk of late and very late scaffold thrombosis (ST).³ However, clinical experience with BVSs outside clinical trials is scarce, and data from “real-world” use are needed. We report our experience with 4 cases of early definite ST in an all-comer population (BVSs have been used as the default drug-eluting device at our institution since April 1, 2013, whenever implantation is deemed technically feasible and clinically indicated).

Case Series

Between April 1, 2013 and March 31, 2014, a total of 339 patients were treated with 504 Absorb BVSs (Abbott Vascular) at our institution. Four cases of definite ST (1.2%) were identified through systematic repeat procedure tracking. All were early thromboses.⁴

All patients were preloaded with generic clopidogrel 300 mg and aspirin 320 mg the day before the procedure (except case #4, who was preloaded immediately before rescue PCI), and received 75 mg and 80 mg daily, respectively, thereafter (during hospitalization and after discharge). None of the patients reported non-adherence to dual-antiplatelet therapy (DAPT) when specifically asked. When ST occurred, clopidogrel was changed to ticagrelor in all cases. All PCIs were guided by online quantitative coronary angiography (QCA) analysis.

Case #1. The first case was a 78-year-old diabetic man who presented with stable angina. He had a previous anterior myocardial infarction. Myocardial perfusion imaging showed moderate ischemia in the inferior wall and a left ventricular ejection fraction (LVEF) of 40%. Elective angiography showed diffuse right coronary artery (RCA) disease, with two severe and distinct stenoses in the mid (71%, type B1) and distal (56%, type C) segments (Figures 1A and 1B). The left coronary artery showed a 40% mid circumflex lesion, and a 60% mid and 80% distal left anterior descending (LAD) lesion (small distal vessel). SYNTAX score was 13. Both RCA lesions were predilated with a 2.5 x 20 mm semicompliant balloon and two non-overlapping 2.5 x 28 mm BVSs were implanted in the distal and mid RCA at 14 atm and 16 atm, respectively. Postdilatation was performed using a 3.0 x 15 mm non-compliant (NC) balloon (14 atm in mid and 12 atm in distal RCA), for a final balloon-to-artery ratio (BAR) of 1.19 (mid RCA) and 1.33 (distal RCA). Final results were considered optimal (Figures 1C and 1D), and the patient was discharged uneventfully the following day. Seven days after PCI, the patient presented with ST-elevation myocardial infarction (STEMI) due to ST in the mid RCA (Figure 1E). Thrombectomy was performed. Optical coherence tomography (OCT) showed no edge dissection, BVS fracture, or malapposition/underexpansion (Figures 1G-1J). Intravenous eptifibatide was administered (double bolus plus infusion). Balloon dilatation of the BVS in the mid RCA was performed using a 3.0 x 20 mm NC balloon at 10 atm, yielding a satisfactory result (thrombolysis in myocardial infarction [TIMI] 3 flow) (Figures 1F, 1K-1N). The BVS in the distal RCA was thrombus free. The patient was event free at follow-up (110 days).

Case #2. The second case was a 37-year-old diabetic man who presented with exertional dyspnea (stable angina equivalent). He had a bare-metal stent in the mid RCA, following an inferior myocardial infarction 3 years earlier. Echocardiography showed a dilated left ventricle, with an LVEF of 30% and moderate mitral regurgitation. Coronary angiography showed a 59% type-B1 lesion in the first diagonal (Figure 2A). The lesion was predilated with a 2.5 x 15 mm semicompliant balloon, followed by implantation of a 2.5 x 28 mm BVS at 16 atm. Postdilatation was performed with a 2.75 x 20 mm NC balloon at 14 atm, for a final BAR of 1.19. Final result was considered optimal (Figure 2B) and the patient was discharged the following day. Four days after the PCI, the patient presented to another hospital with chest pain at rest. Non-ST elevation myocardial infarction (NSTEMI) was diagnosed, and he was transferred, asymptomatic, to our center. Coronary angiography, performed 7 days after BVS implantation, showed BVS thrombotic occlusion (TIMI-0 flow). No PCI was performed and medical treatment was preferred, because it was felt that there would be limited clinical benefit of recanalizing the occluded BVS in light of the limited distal bed and in the absence of recurrent ischemic symptoms since admission. The patient was event free at follow-up (193 days).

Case #3. The third case was a 76-year-old diabetic man who presented with severely limiting dyspnea, moderate aortic stenosis, and concomitant very diffuse and calcified two-vessel CAD: mid LAD chronic total occlusion and a 62% type-C lesion in the distal RCA (Figure 2C). SYNTAX score was 20.5 and LVEF was 60%. He was not considered a surgical candidate due to comorbidities (EuroSCORE II, 9.60%), so he underwent elective PCI of the RCA and LAD. Of note, angiographic image quality was considered suboptimal (body mass index, 37.6 kg/m²). The RCA lesion was predilated using a 2.5 x 12 mm semicompliant balloon. A 3.0 x 28 mm BVS was implanted at 7 atm and postdilated with a 3.0 x 12 mm NC balloon at 22 atm, for a final BAR of 1.11. Final result was considered optimal by the interventionalist, but offline review of the final result by independent observers suggested some degree of focal underexpansion in the distal segment of the BVS and uncovered plaque immediately proximal to the scaffold (42% by QCA, Figure 2D). The LAD lesion was recanalized using antegrade technique and with implantation of two overlapping metallic zotarolimus-eluting stents (2.5 x 18 mm and 3.0 x 22 mm). Four days later, the patient, while still hospitalized, suffered a STEMI due to BVS thrombosis. Stents in the LAD were thrombus free. Thrombectomy catheters could not cross the BVS in the RCA, and dilatation was performed with a 2.0 x 12 mm semicompliant balloon. Signs of dissection were then observed distal to the BVS (possibly caused by the balloon inflation performed during this procedure). Intravenous eptifibatide (double bolus plus infusion) was administered. Two overlapping metallic everolimus-eluting stents (2.5 x 18 mm and 2.5 x 12 mm) were deployed at 12 atm (partially within the BVS). Final flow was TIMI 3. The suspected BVS underexpansion and uncovered plaque might have played a role in the occurrence of BVS thrombosis. The patient was event free at follow-up (96 days).

Case #4. The fourth case was a 56-year-old man who presented late with subacute anterior STEMI at a community hospital. He was transferred to our institution for rescue PCI. Baseline angiography demonstrated an 81% type-B2 proximal LAD lesion with distal TIMI 2 flow (Figure 2E). The lesion was predilated with a 3.0 x 12 mm semicompliant balloon, and a 3.0 x 18 mm BVS was implanted at 14 atm and postdilated with a 3.25 x 12 mm NC balloon at 18 atm, for a final BAR of 1.05. Final result was considered optimal (TIMI 3 flow; Figure 2F). Extensive akinesia of the anterior wall and apex was documented (LVEF, 30%). The patient was transferred back to the referring hospital on DAPT and heparin. The initial procedure was complicated by vascular closure device-induced thrombosis of the right common femoral and external iliac arteries. The patient underwent emergent surgical thrombectomy under DAPT on day 6. One day later, he developed STEMI due to ST. Optical coherence tomography showed no mechanical causes for thrombosis. Thrombectomy and dilatation (3.25 x 12 mm NC balloon at 24 atm) were performed. Final flow was TIMI 2, with diffuse underfilling of the distal bed, likely reflecting extensive necrosis in the LAD distribution. Five days after ST, the patient developed refractory monomorphic ventricular tachycardia that led to asystole. Resuscitation maneuvers were unsuccessful and the patient died.

Discussion

The use of BVS to treat CAD may represent one of the most important innovations since metallic drug-eluting stents. Initial clinical trials have shown that BVSs are associated with a late loss similar to that seen with drug-eluting stent implantation, recovery of vasomotion, and adaptive remodeling once they are completely reabsorbed,^1,2 hinting at the potential for better functional recovery in the long term. Data from BVS trials in stable CAD patients showed similar 3-year clinical outcomes as compared with historical Xience V (Abbott Vascular) data.²

It has been hypothesized that the absence of any residual foreign material and restoration of functional endothelial coverage after BVS reabsorption might reduce the risk of ST.^3,5 Indeed, clinical and experimental data have shown that at 3 years post implantation, BVS struts were completely reabsorbed, and the space they previously occupied was filled with connective tissue.² This process goes in parallel with the recovery of a functional endothelial lining, as demonstrated by vasomotion tests with both endothelium-dependent and endothelium-independent vasoactive agents followed by nitrates.^2,6 Complete reestablishment of the endothelial surface after stent/scaffold implantation is of utmost importance, since it is known that delayed/incomplete endothelialization is the most important risk factor of late thrombosis after drug-eluting stent implantation.^7,8 Moreover, in vitro and animal studies have shown low inflammation and thrombogenicity starting early (<1 week) after implantation of different BVS types.^9-11 Taken together, these data suggest that the risk of ST following BVS implantation might be reduced in comparison with metallic stents at both short and long term.⁵

However, there is also evidence in the literature that hints at an unfavorable peristrut rheology for BVS, as compared with metallic stents. Laser Doppler anemometry data have shown that metallic stents induce laminar flow disruption in proximity to their struts.¹² Similarly, three-dimensional angiographic reconstruction techniques and computational fluid dynamic data showed low shear stress regions and altered flow patterns in-between BVS struts.¹³ It is known that a positive correlation between strut thickness and flow disturbances exists^14,15 and that this relationship carries negative clinical consequences, such as higher restenosis and target vessel revascularization rates.¹⁶ Even though a direct comparison between BVS and metallic stents is not currently available, these flow disturbances could be more pronounced with BVS (struts thickness 150-200 µm³ vs 75-124 µm¹²). In addition, BVS struts typically protrude more in the vessel lumen (as opposed to metallic stent struts, which are frequently embedded in the vessel wall). These concepts are illustrated in Figure 3. Flow disturbance and the resulting low (pathologic) endothelial shear stress are associated with the development and progression of atherosclerosis and endothelial dysfunction.^12,15 Low endothelial shear stress favors regional blood stagnation and modulates local gene expression, promoting a prothrombotic milieu¹⁵ that can predispose to ST. Whether these theoretical considerations will need to be taken into account in clinical practice remains to be determined.

Clinical data on BVS thrombosis (mostly in Absorb-treated cohorts) are summarized in Table 1.^2,17-26 No case of ST was reported in the original ABSORB A cohort up to 5 years²³ or in the ABSORB B cohort up to 3 years.² Other series include short-term follow-up (except in 2 cases^17,21), and only 4 studies included >100 patients,^2,17-19 apart from our report. In the preliminary report of the ABSORB EXTEND trial (450 patients with stable CAD),¹⁷ a total of 4 cases of definite ST were observed (0.9%): 2 cases were early (day 6 and day 27) and 2 cases were late ST (day 75 and day 239). In one case, angiography revealed a thrombus at the site of two overlapping scaffolds. In another, the patient had stopped taking aspirin and clopidogrel. Another case was probably due to clopidogrel resistance. The fourth case occurred in the context of an anaphylactic shock due to bee sting; coronary artery spasm plus eosinophilic reaction could have promoted ST. Gori et al reported 3 cases (2.0%) of early definite ST in a series of acute coronary syndrome patients (n = 150):¹⁸ one case occurred 15 minutes after implantation, another case occurred 3 days later, and the third case occurred within the first month. All 3 patients were on ticagrelor. In 2 of the 3 cases, scaffold underexpansion was observed. In the Prague 19 study,²² the authors reported their experience with BVSs in the setting of STEMI (n = 40). There was 1 case of early definite ST at 13 days post implantation due to cessation of ticagrelor and aspirin by the patient. Finally, Wiebe et al treated 25 STEMI patients with BVS. There was 1 case of definite early ST (2 days post implantation) due to edge dissection.²⁵ Total sample size for the 12 studies presented in Table 1 includes 1393 patients (mostly stable CAD cases and relatively simple lesions), with 13 cases of definite ST (0.9%), which is similar to the 3-year rate of second-generation drug-eluting stent definite thrombosis reported in a recently published “real-world” registry including 7093 patients (1.0%).²⁷ It is interesting to note that 11 out of 13 cases were early ST (8 of them within 1 week of implantation). Moreover, 6 of these 11 cases occurred in patients who received a BVS in the setting of an ACS. Both these findings are also described in two isolated case reports of ST.^28,29 It can be speculated that the prothrombotic milieu of ACS, coupled with the aforementioned unfavorable peristrut rheology of BVS, might promote ST early after implantation, particularly if other concomitant risk factors are present (scaffold malapposition/underexpansion, fracture, overlap or edge dissection, DAPT non-compliance or resistance, small vessel, long scaffold, diabetes, left ventricular dysfunction, chronic renal failure, etc). Indeed, as in many other cases of stent thrombosis, several predisposing factors were present in all 4 of our cases, as shown in Figure 4. 

Understanding the mechanism(s) underlying device thrombosis is crucial to guide its management. Figure 5 outlines the suggested management of ST at our institution. All 4 of our cases were early thromboses (range, 4-7 days). Procedural factors such as scaffold underexpansion/malapposition, fracture, or edge dissection should therefore be considered, as well as issues with DAPT. In only 1 case, scaffold underexpansion was suspected after meticulous offline angiography review (OCT ruled out mechanical factors as a predisposing cause in 2 other cases, a finding also reported by others²⁹). It is important to note that this suspicion was not present during the procedure, in part because image quality was suboptimal due to patient habitus. All our patients received DAPT according to guidelines,³⁰ and they reported compliance with the prescribed DAPT regimen after discharge. Interestingly, at the time of thrombosis, all 4 patients were receiving generic clopidogrel, which has bioequivalence requirements that allow wider variations in maximal serum concentration of clopidogrel bisulfate at steady state.³¹ After ST, all patients were switched to the more potent ticagrelor on clinical grounds (platelet function testing was not felt to alter management at that point), with favorable clinical outcomes except in one case, suggesting that the use of more potent DAPT, whenever possible, should be considered.

Conclusion

Definite ST appears to be an infrequent complication after BVS implantation, with an incidence similar to second-generation drug-eluting stent thrombosis. Upon detailed analysis of the 4 definite ST cases that we have documented, we draw the following conclusions: (1) multiple risk factors of stent thrombosis were present in all 4 cases; (2) all patients were treated with generic clopidogrel; and (3) scaffold underexpansion might be more difficult to identify, particularly when intravascular imaging is not used (as is the case in the majority of BVS implantations). Therefore, when BVS implantation is performed in patients with multiple risk factors for stent thrombosis, and especially in ACS patients, we recommend: (1) the use of a more potent antiplatelet regimen whenever clinically indicated (eg, aspirin plus ticagrelor or prasugrel); and (2) ample utilization of online QCA and intravascular imaging technologies to optimize device deployment.

References

1. Sarno G, Bruining N, Onuma Y, et al. Morphological and functional evaluation of the bioresorption of the bioresorbable everolimus-eluting vascular scaffold using IVUS, echogenicity and vasomotion testing at two year follow-up: a patient level insight into the ABSORB A clinical trial. Int J Cardiovasc Imaging. 2012;28(1):51-58. 
2. Serruys PW, Onuma Y, Garcia-Garcia HM, et al. Dynamics of vessel wall changes following the implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months. EuroIntervention. 2014;9(11):1271-1284. 
3. Iqbal J, Onuma Y, Ormiston J, Abizaid A, Waksman R, Serruys P. Bioresorbable scaffolds: rationale, current status, challenges, and future. Eur Heart J. 2013;35(12):765-776. 
4. Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351. 
5. Onuma Y, Serruys PW. Bioresorbable scaffold: the advent of a new era in percutaneous coronary and peripheral revascularization? Circulation. 2011;123(7):779-797. 
6. Serruys PW, Ormiston JA, Onuma Y, et al. A bioabsorbable everolimus-eluting coronary stent system (ABSORB): 2-year outcomes and results from multiple imaging methods. Lancet. 2009;373(9667):897-910. 
7. Finn AV, Joner M, Nakazawa G, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation. 2007;115(18):2435-2441. Epub 2007 Apr 16.
8. Joner M, Finn AV, Farb A, et al. Pathology of drug-eluting stents in humans: delayed healing and late thrombotic risk. J Am Coll Cardiol. 2006;48(1):193-202. Epub 2006 May 5.
9. Schultz RK. REVA Medical, Inc. Bioresorbable stent. Presented at: Cardiovascular Revascularization Therapies Conference. Washington, DC. March 7-9, 2007.
10. Heublein B, Rohde R, Kaese V, Niemeyer M, Hartung W, Haverich A. Biocorrosion of magnesium alloys: a new principle in cardiovascular implant technology? Heart. 2003;89(6):651-656. 
11. Seifert B, Romaniuk P, Groth T. Bioresorbable, heparinized polymers for stent coating: in vitro studies on heparinization efficiency, maintenance of anticoagulant properties and improvement of stent haemocompatibility. J Mater Sci Mater Med. 1996;7:465-469. 
12. Dörler J, Frick M, Hilber M, et al. Coronary stents cause high velocity fluctuation with a flow acceleration and flow reduction in jailed branches: an in vitro study using laser-Doppler anemometry. Biorheology. 2012;49(5-6):329-340. 
13. Gogas BD, King SB, Timmins LH, et al. Biomechanical assessment of fully bioresorbable devices. JACC Cardiovasc Interv. 2013;6(7):760-761. 
14. LaDisa JF, Olson LE, Guler I, et al. Stent design properties and deployment ratio influence indexes of wall shear stress: a three-dimensional computational fluid dynamics investigation within a normal artery. J Appl Physiol (1985). 2004;97(1):424-430. 
15. Koskinas KC, Chatzizisis YS, Antoniadis AP, Giannoglou GD. Role of endothelial shear stress in stent restenosis and thrombosis: pathophysiologic mechanisms and implications for clinical translation. J Am Coll Cardiol. 2012;59(15):1337-1349. 
16. Kastrati A, Mehilli J, Dirschinger J, et al. Intracoronary stenting and angiographic results: strut thickness effect on restenosis outcome (ISAR-STEREO) trial. Circulation. 2001;103(23):2816-2821. 
17. Ishibashi Y, Onuma Y, Muramatsu T, et al. Lessons learned from acute and late scaffold failures in the ABSORB EXTEND trial. EuroIntervention. 2014;10(4):449-457. 
18. Gori T, Schulz E, Hink U, et al. Early outcome after implantation of Absorb bioresorbable drug-eluting scaffolds in patients with acute coronary syndromes. EuroIntervention. 2014;9(9):1036-1041. 
19. Abizaid A. First report on the pivotal DESolve Nx trial: 6-month clinical and multimodality imaging results. Presented at: EuroPCR. Paris, France. May 21-24, 2013.
20. Diletti R, Karanasos A, Muramatsu T, et al. Everolimus-eluting bioresorbable vascular scaffolds for treatment of patients presenting with ST-segment elevation myocardial infarction: BVS STEMI first study. Eur Heart J. 2014;35(12):777-786. Epub 2014 Jan 6.
21. Haude M. Two-year clinical data and multi-modality imaging results up to 1-year follow-up of the BIOSOLVE-I study with the paclitaxel-eluting bioabsorbable magnesium scaffold (DREAMS). Presented at: EuroPCR. Paris, France. May 21-24, 2013.
22. Kocka V, Maly M, Tousek P, et al. Bioresorbable vascular scaffolds in acute ST-segment elevation myocardial infarction: a prospective multicentre study “Prague 19.” Eur Heart J. 2014;35(12):787-794. Epub 2014 Jan 12.
23. Onuma Y, Dudek D, Thuesen L, et al. Five-year clinical and functional multislice computed tomography angiographic results after coronary implantation of the fully resorbable polymeric everolimus-eluting scaffold in patients with de novo coronary artery disease: the ABSORB cohort A trial. JACC Cardiovasc Interv. 2013;6(10):999-1009. 
24. Costa RA. REVA ReZolve clinical program update. Presented at: Transcatheter Cardiovascular Therapeutics. Miami Beach, FL. October 22-28, 2012.
25. Wiebe J, Möllmann H, Most A, et al. Short-term outcome of patients with ST-segment elevation myocardial infarction (STEMI) treated with an everolimus-eluting bioresorbable vascular scaffold. Clin Res Cardiol. 2014;103(2):141-148. Epub 2013 Oct 18.
26. Kajiya T, Liang M, Sharma RK, et al. Everolimus-eluting bioresorbable vascular scaffold (BVS) implantation in patients with ST-segment elevation myocardial infarction (STEMI). EuroIntervention. 2013;9(4):501-504. 
27. Tada T, Byrne RA, Simunovic I, et al. Risk of stent thrombosis among bare-metal stents, first-generation drug-eluting stents, and second-generation drug-eluting stents: results from a registry of 18,334 patients. JACC Cardiovasc Interv. 2013;6(12):1267-1274. 
28. Jaguszewski M, Wyss C, Alibegovic J, Lüscher TF, Templin C. Acute thrombosis of bioabsorbable scaffold in a patient with acute coronary syndrome. Eur Heart J. 2013;34(27):2046. Epub 2013 Feb 17.
29. Fernández-Rodríguez D, Brugaletta S, Otsuki S, Sabaté M. Acute Absorb bioresorbable vascular scaffold thrombosis in ST-segment elevation myocardial infarction: to stent or not to stent? EuroIntervention. 2014;10(5):600; discussion 600.
30. Levine GN, Bates ER, Blankenship JC, et al. 2011 ACCF/AHA/SCAI guideline for percutaneous coronary intervention: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58(24):e44-e122. Epub 2011 Nov 7.
31. Di Girolamo G, Czerniuk P, Bertuola R, Keller GA. Bioequivalence of two tablet formulations of clopidogrel in healthy Argentinian volunteers: a single-dose, randomized-sequence, open-label crossover study. Clin Ther. 2010;32(1):161-170. 

From the Interventional Cardiology Division, Department of Medicine, Montreal Heart Institute, University of Montreal, Montreal, QC, Canada.

Funding: Dr Azzalini is funded by a grant of the Spanish Society of Cardiology. Dr L’Allier is supported by La Fondation de l’Institut de cardiologie de Montréal and holds the Desgroseillers-Bérard Chair in Interventional Cardiology.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted June 26, 2014, provisional acceptance given June 30, 2014, final version accepted July 2, 2014.

Address for correspondence: Philippe L. L’Allier, MD, Desgroseillers-Bérard Chair in Interventional Cardiology, University of Montreal, Director, Interventional Cardiology, Department of Medicine, Montreal Heart Institute, 5000 Bélanger Est – Montréal, Québec, H1T 1C8 Canada. Email: philippe.lallier@icm-mhi.org