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Genetics, coronary artery disease, and myocardial revascularization: will novel genetic risk scores bring new answers?

  • Sonya Kit Hui
  • Louise Sun
  • Marc RuelEmail author
Review Article
  • 49 Downloads

Abstract

Both percutaneous coronary intervention (PCI) and coronary artery bypass graft surgery (CABG) are options for revascularization in multi-vessel coronary artery disease (CAD). However, the best form of revascularization remains controversial. Results from clinical trials (FREEDOM, SYNTAX, NOBLE, EXCEL) have identified factors related to CAD severity such as diabetes and SYNTAX score as indicators that patients may have better outcomes with CABG compared to PCI. Nevertheless, the discovery of other predictors of optimal revascularization therapy is necessary to improve decision-making and personalize the treatment of multi-vessel CAD. Genome-wide association studies have identified numerous previously unknown DNA variants that increase predisposition for CAD. Recently, a composite polygenic risk score has been developed to better assess the relative contribution of multiple SNPs and quantify overall genetic risk for CAD. High polygenic risk score is associated with increased coronary events and greater benefit from statin therapy in large observational studies. This effect is independent from traditional cardiovascular risk factors. At the same time, randomized clinical trials have shown that CAD severity is a determinant of optimal revascularization treatment. It remains unknown whether polygenic risk score is robustly associated with increased CAD severity at presentation, and whether this score can be used to identify patients who will show greater benefit from revascularization with CABG or with PCI.

Keywords

Coronary artery disease Genetics Polygenic risk score 

Revascularization for multi-vessel coronary artery disease

Cardiovascular disease is the leading cause of death worldwide. Even with secondary prevention and optimal medical therapy (OMT), many patients with CAD go on to develop activity-limiting symptoms and/or are found to have advanced disease, requiring revascularization. Among patients with multi-vessel CAD, both percutaneous coronary intervention (PCI) and CABG are options for revascularization treatment. However, which of PCI or CABG offers the ideal form of revascularization for multi-vessel CAD remains a complex and controversial topic.

The revascularization decision-making process is influenced by individual patient characteristics (age, functional status, clinical presentation, cardiac function, diabetes, renal function, tolerance for dual antiplatelet therapy), comorbidities, variation in anatomic location and extent of stenotic atherosclerotic lesions, the likelihood of complete revascularization, technical aspects of PCI and CABG procedures, and patient expectations and preferences [1]. This is further confounded by recent advances in both forms of revascularization, such as the advent of second-generation drug eluting stents (DES), the use of fractional flow reserve measurements, the optimization of PCI with intravascular ultrasound and optical coherence tomography, and the advent of new antiplatelet and antithrombotic agents, as well as by the use of multiple arterial grafts, off-pump surgery and minimally invasive procedures with CABG.

The main randomized clinical trials that have examined PCI vs. CABG for revascularization of multi-vessel disease during the last decade are the SYNTAX and FREEDOM trials [2]. Recently, the NOBLE and EXCEL trials were published, but their results are in part contradictory and incomplete (in the case of EXCEL), and overall, these trials provide limited, if any, novel practice-changing information [3].

SYNTAX score and revascularization

The SYNTAX trial evaluated outcomes in 1800 patients with severe CAD and a mean age of 65, who were randomly assigned to revascularization with either PCI or with CABG. At 1-year follow-up, CABG was associated with decreased rates of revascularization compared to PCI, in patients with triple-vessel CAD, left main disease, or both [4]. At 5-year follow-up, patients with triple-vessel CAD who received CABG had decreased rates of death, myocardial infarction, and repeat revascularization compared to PCI, albeit with one important caveat: their SYNTAX score at study inception had to be over 22 for a significant benefit to occur [5]. The SYNTAX scoring system is based on angiographic factors such as quantity, complexity, and localization of coronary lesions [4]. It has become a well-accepted indicator of anatomical CAD extent and severity. As a result, CAD complexity as indicated by SYNTAX score has become one determinant of which revascularization treatment should be considered in patients with multi-vessel CAD, as is now reflected in Heart Team discussions and best practice guidelines around the world [6].

However, the results of the SYNTAX trial must be interpreted within the context of its limitations. For instance, the study population was predominantly male. Additionally, a large proportion of SYNTAX patients had complex CAD, with 70% exhibiting bifurcation lesions and 20% with chronic total occlusions [7]. Patients in the PCI arm also received first-generation DES (Taxus) [4], which are associated with higher rates of restenosis and stent thrombosis compared to current, second-generation DES (everolimus, zotarolimus) [7]. Furthermore, patients in the CABG arm had sub-optimal medical therapy. Only 15% of patients in the CABG arm had off-pump CABG (which is associated with less strokes [8]), only 63.2% had complete revascularization, and 27.6% had multi-arterial grafts [7]. Although a large parallel registry overwhelmingly indicated better outcomes with CABG, a greater number of CABG patients withdrew consent or were lost to follow-up compared to the PCI group [7]. Finally, when patients with triple-vessel CAD are excluded, results show comparable mortality between patients with left main disease after PCI vs. CABG [9].

The SYNTAX scoring system has also been criticized for not integrating clinical or physiological factors. Enhanced versions of the SYNTAX score have been developed which also include baseline clinical variables (i.e., left ventricular ejection fraction, unprotected left main disease, creatinine clearance, peripheral arterial disease, female sex and chronic obstructive pulmonary disease) [10] or functional flow reserve measurements [7]. Results show that these modified scores can lead to reclassification of patients and can better predict outcomes with more accuracy than SYNTAX score alone [7]. Therefore, despite compelling results from the SYNTAX trial, the study is not without important limitations, and its general applicability as a predictor of outcomes in patients with multi-vessel disease should not be overstated.

Left main disease and revascularization

More recently, the NOBLE trial compared outcomes after PCI vs. CABG in patients with left main disease. Five-year estimates showed more frequent major adverse cardiac or cerebrovascular events in patients with PCI compared to CABG [11]. However, similar to the SYNTAX trial, patients in the PCI arm received a type of DES that may be associated with slightly higher restenosis and thrombosis rates [2]. Another study called the EXCEL trial also randomized patients with left main disease to undergo PCI or CABG, but utilized second-generation DES (everolimus). The initial 3-year results of the EXCEL trial demonstrate that if patients with left main disease are stratified by SYNTAX score, those with low to intermediate CAD complexity (SYNTAX score < 32) may have no differences in outcomes between PCI and CABG at up to 3 years of follow-up [12]. However, worrisome trends toward higher event rates with PCI were noted, and 5-year results are soon pending. Long-term follow-up of EXCEL is therefore needed to confirm whether left main disease is associated with equivalent late outcomes after PCI vs. CABG.

Diabetes and revascularization

Diabetes is strongly associated with CAD. The FREEDOM trial compared outcomes (composite of all-cause mortality, myocardial infarction, and stroke) after PCI vs. CABG in 1900 patients with multi-vessel CAD and diabetes. At 5 years, more frequent adverse outcomes, including all-cause death, were found in the PCI group compared to the CABG group, regardless of SYNTAX score, left ventricular ejection fraction, and renal function [13].

Recently, a pooled analysis of three separate trials of patients with diabetes and stable CAD (BARI 2D, COURAGE, and FREEDOM) was published examining OMT as an additional treatment in addition to PCI and CABG. Using a composite outcome of death, myocardial infarction, or stroke, results showed that the combination of CABG + OMT had better outcomes than PCI + OMT or OMT alone at a median follow-up of 4.5 years [1]. In summary, it has been established in the literature that CABG is the optimal form of revascularization for diabetic patients with multi-vessel CAD. As such, CABG is recommended over PCI for patients with multi-vessel CAD and diabetes in current practice guidelines [6].

Similar to SYNTAX score, it is postulated that diabetes is linked to better outcomes with CABG vs. PCI because of generally increased CAD severity in diabetes. It is well known that patients with diabetes or impaired glucose tolerance have more extensive CAD on coronary angiography (number of lesions, Gensini score) compared to patients with normal glucose tolerance [14]. Multiple mechanisms contribute to increased CAD severity in diabetes, such as vascular inflammation, metabolic and oxidative stress, leading to microvascular dysfunction, impaired angiogenesis of collaterals, increased propensity for restenosis, plaque instability, more diffuse and extensive disease, and an enhanced potential for progression to diastolic or systolic heart failure [15]. Additionally, it has been shown that patients with diabetes have decreased myocardial flow reserve compared to patients without diabetes, even after controlling for SYNTAX score [16]. Patients with diabetes display an increased incidence of restenosis, greater progression of CAD, and a higher risk of myocardial infarction and death after PCI [17]. This has been postulated to be due to increased stimulation of vascular smooth muscle cell growth factors leading to augmented intimal hyperplasia [18]. After CABG, patients with diabetes show increased rates of nonfatal adverse outcomes and death compared to patients without diabetes [19, 20, 21]. However, regardless of having generally worse outcomes, patients with diabetes and multi-vessel disease still have better outcomes after CABG vs. PCI when comparing different treatment groups.

Factors favoring CABG for multi-vessel coronary artery disease

In parallel with randomized controlled trials, large-scale observational studies also suggest that CABG is generally associated with improved outcomes compared to PCI in patients with severe multi-vessel CAD [22, 23, 24, 25]. Although CABG is generally associated with more stroke compared to PCI, anaortic off-pump CABG has a significantly lower incidence of stroke (0.4% at 30-day post-op) [8]. Overall, CABG is generally considered more beneficial in patients with multi-vessel disease who exhibit anatomically complex, diffuse disease, a large amount of ischemic myocardium, decreased left ventricular systolic function, and high risk for adverse cardiovascular events [26].

However, CABG is not a benign revascularization procedure. Despite factors favoring CABG with regard to long-term outcomes, open heart surgery remains an invasive, major surgical procedure that involves the creation of a sternotomy, the use of cardiopulmonary bypass, and a long recovery period, in most cases. The overall rate of operative mortality is estimated at 1 to 3% for all patients [23, 27] and depends on the extent of comorbidities, left ventricular function, age, renal function, type and number of bypass grafts, and institutional expertise [28, 29, 30, 31, 32]. For these reasons, CABG is not always the preferred treatment option for some patients with severe multi-vessel disease, despite its association with beneficial outcomes.

Factors favoring PCI for multi-vessel coronary artery disease

Compared to CABG, PCI has a rate of operative mortality between 1.2 and 1.4% [33, 34] and has been associated with less risk of stroke in a number of randomized clinical trials including SYNTAX and FREEDOM. As such, PCI may be a more suitable procedure for patients with a history of cerebrovascular disease, or for those who are particularly stroke-averse. PCI is also a much less invasive procedure that is associated with lower peri-procedural morbidity, and an easier and faster recovery. PCI is therefore better tolerated by patients with poor functional status and significant comorbidities, i.e., those with increased operative risk who may not be able to safely undergo CABG. For these reasons, PCI is generally preferred by many patients and physicians despite its limitations. In patients with multi-vessel disease with low SYNTAX score and without diabetes, PCI remains a strong and potentially superior form of revascularization treatment.

Recommendations for revascularization

Studies thus far in patients with multi-vessel disease indicate that the severity of CAD, as denoted by anatomical SYNTAX score or comorbid diabetes, is a determinant of outcomes after revascularization. CABG is thought to be advantageous in patients with more severe CAD because it bypasses lesions of any complexity, and is a more definitive, thorough form of revascularization compared to PCI [26]. While PCI uses cutting-edge pharmacology and technology to target the culprit lesion, the rate of restenosis or native CAD progression is between 10 and 30%, and the procedure is not prophylactic against future lesions [26]. By bypassing an entire segment of coronary artery, CABG not only treats the culprit lesion but also protects against vulnerable plaques that may cause future events by way of distally positioned grafts. Therefore, guidelines currently recommend that patients with multi-vessel CAD undergo CABG over PCI in the presence of diabetes, SYNTAX score > 22, distal left main disease, or left ventricular dysfunction [6, 35, 36]. However, it remains unclear which form of revascularization is superior in other subsets of patients with multi-vessel CAD, such as those with SYNTAX score < 22 and without diabetes.

Need for greater personalization of revascularization

In summary, the decision to undergo PCI or CABG for revascularization of multi-vessel CAD is not a straightforward one. It involves the consideration and integration of several factors, such as an increased risk of stroke with CABG compared to an increased risk of myocardial infarction and repeat revascularization with PCI [37]. Ideally, this decision should be evidence-based, individualized to the clinical specifics of each case, made with the balanced expertise of a multidisciplinary Heart Team, and placed in the context of the patient’s values and preferences. The discovery of additional predictors of optimal revascularization therapy with incremental value is crucial to optimize surgical vs. interventional vs. medical decision-making and to better personalize the treatment of multi-vessel CAD.

Genetic basis of coronary artery disease

Lifestyle-related comorbidities such as hypertension, dyslipidemia, diabetes, obesity, peripheral vascular disease, and smoking are well established as traditional risk factors for CAD. In addition to these known contributors, scientific research has demonstrated that inherited genetic factors also significantly influence the development of CAD. Multiple common genetic variants have recently been uncovered that cumulatively increase risk for CAD [38]. This genetic contribution to CAD is significant, with both rare and common genetic variants shown to account for over 50% of susceptibility to CAD [39]. However, these recent scientific findings regarding the genetic basis of CAD have yet to be translated to clinical practice.

9p21risk locus and coronary artery disease

In 2007, a novel risk locus for CAD was identified on chromosome 9p21, using a genome-wide association approach by Dr. Ruth McPherson’s group at the University of Ottawa Heart Institute. The risk locus encompasses multiple single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium spanning 58 kb and exerts its effects independently of all known CAD risk factors, suggesting a novel biological pathway relevant to CAD [40]. About 25% of the population carry two copies of the risk allele and have a twofold increased risk of premature CAD and a 50% increased risk of later-onset CAD. Although it was originally discovered in cohorts of European ancestry, the 9p21 risk allele has now been validated in multiple ethnic populations [41]. Overall, the 9p21 risk allele has been established as a prominent risk factor for significantly increased burden of coronary atherosclerosis as indicated by angiography (Fig. 1) and coronary events.
Fig. 1

Association of 9p21 gene dosage with severity of CAD [42]. a Proportion of early-onset CAD patients with 3VD as a function of genotype (n = 340). b Proportion of early-onset patients with 1VD as a function of genotype (n = 384). c Proportion of late-onset patients with 3VD as a function of genotype (n = 293). d Proportion of late-onset patients with 1VD as a function of genotype (n = 215). e Proportion of all patients with 3VD as a function of genotype (n = 633). Among non-risk/non-risk patients, 30% have 3VD. f Proportion of all patients with 1VD as a function of genotype (n = 518). Early onset: M < 55 years and F < 65 years with one epicardial stenosis ≥ 50%, age = 56.1 ± 9.6 years; late onset: patient age = 70.0 ± 8.0 years. AA risk/risk, AB risk/non-risk, BB non-risk/non-risk

Given the association with CAD severity, studies have been conducted to examine the relationship between 9p21 expression and outcomes after revascularization. Although two separate studies have demonstrated that 9p21 risk alleles are associated with earlier and more extensive CAD, there was no apparent association with outcomes at 3 years of follow-up after PCI or CABG [43, 44]. This may be because 3 years is not a long enough duration of follow-up in order to observe differences in outcomes due to 9p21 genotype. Alternatively, although the mechanism of 9p21’s effect on CAD has not been established, it has been postulated to modify the regulation of vascular smooth muscle proliferation. It is possible that the specific role that the 9p21 locus plays in CAD pathogenesis only directly impacts the formation of disease, rather than outcomes after revascularization treatment. To this end, more comprehensive genetic risk assessment in addition to 9p21 genotype is required to risk-stratify patients with CAD and predict outcomes after treatment with OMT, PCI, and CABG.

Polygenic risk score for coronary artery disease

In the last decade, sequential genome-wide association studies have identified numerous additional novel genetic variants in addition to 9p21 that significantly increase predisposition for CAD. In order to assess the cumulative effect of multiple genetic variants, a composite polygenic risk score can be calculated by combining the number and effect size of all known risk alleles and used to quantify overall genetic risk for CAD [45]. Polygenic risk scores for breast cancer have been utilized in the oncology literature to risk-stratify individuals for incidence and mortality of breast cancer and to determine screening and preventative treatment strategies [46, 47, 48]. Polygenic risk scores for CAD are associated both with incident and recurrent CAD events such as cardiovascular death, myocardial infarction, unstable angina, and revascularization [45]. The association of polygenic risk score and increased CAD susceptibility has been shown to be independent of lifestyle factors such as smoking, obesity, physical activity, and diet in three different cohorts: participants of the Malmö Diet and Cancer Study, Atherosclerosis Risk in Communities Study, and Women’s Genome Health Study [49]. A recent meta-analysis has demonstrated that high polygenic score is also associated with a greater burden of subclinical coronary atherosclerosis as determined by coronary artery calcification [50]. There are currently no studies evaluating the association of polygenic risk score with CAD risk specifically in India. However, a recent study has shown preliminary findings associating certain SNPs with particular clinical phenotypes of CAD in an Indian population from Hyderabad [51]. Despite the association of polygenic risk score with CAD prevalence and severity, it is unknown whether high polygenic risk score is associated with worse outcomes after revascularization (in-stent restenosis/thrombosis with PCI, graft vasculopathy, or other complications after CABG) compared to low or intermediate genetic risk.

There are significant challenges to consider regarding the incorporation of polygenic risk score for coronary artery disease into clinical practice. The availability of resources for genetic testing and counseling is limited and associated with significant cost. Genetic risk scores integrate rapidly advancing scientific findings and will continue to evolve with the discovery of more SNPs associated with CAD. Therefore, genetic risk score is not a fixed value—there is a need to continuously re-evaluate genetic risk for CAD from a patient’s genome sequencing. There were concerns about the potential psychological impact of disclosing genetic risk to patients with coronary artery disease, but studies have shown a lack of negative impact on psychological wellbeing [52]. Interestingly, disclosure of genetic risk provides some benefit, in that patients with high genetic risk show increased compliance with statin therapy and lower LDL levels [53], but no significant improvement in lifestyle-related behavior such as diet and exercise [54]. Although there is a strong body of research robustly validating the association of genetic risk score with CAD risk, current guidelines do not mandate the assessment of genetic risk score in clinical practice, as these findings have not translated into a significant impact on cardiovascular care [55]. Guidelines are unlikely to change to incorporate routine risk stratification with polygenic risk score unless studies demonstrate a significant impact on clinical decision-making.

Importantly, recent studies show that high polygenic risk score is associated with greater benefit from statin therapy among patients with CAD [45, 50]. Patients classified as having a high polygenic risk score (top quintile of distribution) demonstrate significantly greater absolute and relative risk reduction (prevention of myocardial infarction and death resulting from coronary heart disease) with statin therapy compared to all others. This effect of polygenic risk score persists despite adjusting for traditional cardiovascular risk factors, demonstrating that polygenic risk has incremental value as a predictor of CAD severity and response to treatment. As such, risk stratification of patients by polygenic risk score has the potential for personalizing clinical management of CAD.

Furthermore, expanded polygenic risk scores incorporating a greater number of SNPs demonstrate improved accuracy for predicting CAD events. A recently published manuscript by the CARDIoGRAM+C4D [Coronary ARtery DIsease Genome wide Replication and Meta-analysis (CARDIoGRAM) plus The Coronary Artery Disease (C4D) Genetics] consortium, a collaborative effort that combines data from multiple large-scale genetic studies to identify risk loci for CAD, has established a total of 243 SNPs significantly associated with CAD at a false discovery rate (FDR) q < 0.05 (Fig. 2) [56]. However, an expanded polygenic risk score for CAD has yet to be developed or utilized incorporating this recently published list of 243 SNPs. Previous studies show that a 57-SNP polygenic risk score can identify patients at highest risk of CAD who demonstrate greater benefit from statin therapy [38]. It is unknown whether an expanded 243-SNP polygenic risk score is even more robustly associated with increased CAD severity and could be used to identify patients who will show greater benefit from revascularization with CABG or with PCI.
Fig. 2

Association analyses based on false discovery rate implicate 243 susceptibility loci for coronary artery disease [56]. Genome-wide association studies (GWAS) in CAD have identified 66 loci at “genome-wide significance” (P < 5 × 10−8) but a much larger number of putative loci at a false discovery rate (FDR) of 5%. An interim release of UK Biobank (UKBB) data was used to evaluate the validity of the FDR approach. A CAD phenotype inclusive of angina (SOFT; Ncases = 10,801) was selected for conducting a meta-analysis with the two most recent CAD GWASs. Transposed Manhattan plot is shown with the SOFT meta-analysis results under an additive model. P values are truncated at –log10(P) = 20. Red dotted lines are at GWAS (P = 5 × 10−8) and 5% FDR significance (P = 6.28 × 10−5). Known CAD risk loci are shown in black. Exome chip markers are shown with an asterisk. The 13 novel CAD loci which reached genome-wide significance are written in brown. The set of 304 independent variants at 5% FDR in this study identified 243 loci that implicate pathways in blood vessel morphogenesis as well as lipid metabolism, nitric oxide signaling, and inflammation

Polygenic risk score and outcomes after revascularization

Evidence from randomized clinical trials suggests that the severity of CAD is one determinant of which revascularization treatment is best for a given patient. For instance, CABG appears to constitute a more durable form of revascularization compared to PCI in the context of advanced multi-vessel CAD, as it is associated with better outcomes in patients with comorbid diabetes and high anatomical SYNTAX score [5, 13]. It is crucial, however, to determine which other predictors of outcomes after PCI vs. CABG can direct clinical decision-making for patients with multi-vessel CAD.

In this regard, polygenic risk score for CAD has been validated as a marker of increased CAD severity as defined by clinical events as well as by measured coronary artery calcification [50]. Moreover, polygenic risk score has been used to successfully select patients with CAD who demonstrate increased benefit from statin therapy compared to others [45, 50]. Finally, an expanded 243-SNP polygenic risk score for CAD based on recent analyses published by the CARDIoGRAM+C4D consortium may have incremental value and convey inherent CAD risk and severity more meaningfully than SYNTAX score or diabetes [56].

Recent data published by the CARDIoGRAM+C4D consortium can be used to develop an expanded 243-SNP polygenic risk score for CAD. A 243-SNP polygenic risk score may serve as a valuable indicator of whether patients with multi-vessel CAD would benefit more from revascularization by CABG or by PCI. Currently, it is unknown whether high polygenic risk score is associated with differential outcomes after CABG, after PCI, or with OMT, regardless of underlying CAD severity. As such, this topic is the focus of an ongoing study by the authors of this article.

Future directions

It is crucial to uncover factors that predict outcomes after OMT, PCI, and CABG in order to offer the best treatment recommendations to patients with multi-vessel CAD. Polygenic risk scores for CAD apply the latest findings in genetic research, measure the cumulative genetic susceptibility of an individual for CAD, and have been established as predictors of incident CAD and CAD mortality. Risk-stratifying patients by an expanded 243-SNP polygenic risk score may demonstrate an association with CAD severity as indicated by both their clinical presentation and the degree of lesions on coronary angiography. As such, patients with high polygenic risk score may have better outcomes after CABG compared to PCI and/or OMT due to increased CAD aggressiveness. Translational research studies successfully validating the association of high polygenic risk score with outcomes after revascularization would apply cutting-edge cardiovascular genomics to potentially guide clinical practice and provide better indications for revascularization treatment.

Furthermore, polygenic risk score may be of incremental value in that it conveys inherent CAD severity in addition to SYNTAX score and diabetes [42]. Future studies could validate 243-SNP polygenic risk score as a selector of patients with multi-vessel disease who will obtain greater benefit from CABG compared to PCI for revascularization. Based on the current literature, we propose that targeting heritable causes of CAD through the evaluation of an individual patient’s genotypes could prove to be an effective strategy for personalizing revascularization decision-making, improving treatment for patients with multi-vessel CAD. On the contrary, it is also possible that high polygenic risk score may not be associated with worse outcomes in patients with CAD, or a difference in outcomes between treatment groups. Even so, such research would clarify that the impact of cumulative genetic risk is limited to the earlier stages of CAD onset and progression, and would cease to significantly impact outcomes once treatment is initiated. Regardless, future studies on this topic are merited to elucidate the importance of the contribution of overall genetic risk to CAD pathogenesis, treatment, and outcomes.

Notes

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© Indian Association of Cardiovascular-Thoracic Surgeons 2018

Authors and Affiliations

  1. 1.Division of Cardiac Surgery, University of Ottawa Heart InstituteUniversity of OttawaOttawaCanada
  2. 2.Division of Cardiac Anesthesiology, Department of Anesthesiology and Pain MedicineUniversity of Ottawa Heart InstituteOttawaCanada

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