Publications by authors named "Filio Billia"

63 Publications

MACHINE LEARNING COMPARED TO CONVENTIONAL STATISTICAL MODELS FOR PREDICTING MYOCARDIAL INFARCTION READMISSION AND MORTALITY: A SYSTEMATIC REVIEW.

Can J Cardiol 2021 Mar 4. Epub 2021 Mar 4.

Ted Rogers Centre for Heart Research; Peter Munk Cardiac Centre of University Health Network; ICES; Institute for Health Policy, Management and Evaluation; Toronto General Hospital Research Institute; University of Toronto. Electronic address:

Background: To review the performance of machine learning (ML) methods compared to conventional statistical models (CSM) for predicting readmission and mortality in patients with myocardial infarction (MI).

Methods: Following PRISMA guidelines, we systematically reviewed the literature search using MEDLINE, EPUB, Cochrane CENTRAL, EMBASE, INSPEC, ACM Library, and Web of Science. Eligible studies included primary research articles published between January 2000 and March 2020, comparing ML and CSM for prognostication after MI.

Results: Of 7,348 articles, 112 underwent full-text review, with the final set comprised of 24 articles and 374,365 patients. ML methods included artificial neural networks (n=12 studies), random forests (n=11), decision trees (n=8), support vector machines (n=8) and Bayesian techniques (n=7). CSM included logistic regression (n=19 studies), existing CSM-derived risk scores (n=12) and Cox regression (n=2). Thirteen of 19 studies examining mortality reported higher c-indices using ML compared to CSM. One study examined readmissions at two different time points, with c-indices that were higher for ML than CSM. Across all studies, a total of 29 comparisons were performed, but the majority (n=26, 90%) found small (< 0.05) absolute differences in the c-index between ML and CSM. Using a modified CHARMS checklist, sources of bias were identifiable in the majority of studies, and only 2 were externally validated.

Conclusion: Although ML algorithms tended to have higher c-indices than CSM for predicting death or readmission after MI, these studies exhibited threats to internal validity and were often unvalidated. Further comparisons are needed, with adherence to clinical quality standards for prognosis research.
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http://dx.doi.org/10.1016/j.cjca.2021.02.020DOI Listing
March 2021

Left Ventricular Assist Device Support for Fabry Cardiomyopathy: A Case Series.

CJC Open 2021 Feb 6;3(2):201-203. Epub 2020 Oct 6.

Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.

Patients with restrictive cardiomyopathy due to Fabry disease are often deemed ineligible for left ventricular assist device (LVAD) support due to the risk of suction events with a small LV cavity. We describe the first case series of LVAD support for Fabry disease. LVAD therapy can improve survival, quality of life, and provide clinical stability to start enzyme replacement therapy. Precautions at the time of surgery include rapid treatment of fever to avoid Fabry crises, involvement of a multidisciplinary team, and early initiation of rehabilitation. We describe LVAD support for both bridging and destination therapy.
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http://dx.doi.org/10.1016/j.cjco.2020.09.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7893197PMC
February 2021

Mortality in patients with cardiogenic shock supported with VA ECMO: A systematic review and meta-analysis evaluating the impact of etiology on 29,289 patients.

J Heart Lung Transplant 2021 Apr 19;40(4):260-268. Epub 2021 Jan 19.

Ted Rogers Center of Excellence, Peter Munk Cardiac Centre, Toronto, Ontario, Canada.

Background: Venoarterial extracorporeal membrane oxygenation (VA ECMO) is associated with variable outcomes. In this meta-analysis, we evaluated the mortality after VA ECMO across multiple etiologies of cardiogenic shock (CS).

Methods: In June 2019, we performed a systematic search selecting observational studies with ≥10 adult patients reporting on short-term mortality (30-day or mortality at discharge) after initiation of VA ECMO by CS etiology published after 2009. We performed meta-analyses using random effect models and used metaregression to evaluate mortality across CS etiology.

Results: We included 306 studies (29,289 patients): 25 studies on after heart transplantation (HTx) (771 patients), 13 on myocarditis (906 patients), 33 on decompensated heart failure (HF) (3,567 patients), 64 on after cardiotomy shock (8,231 patients), 10 on pulmonary embolism (PE) (221 patients), 80 on acute myocardial infarction (AMI) (7,774 patients), and 113 on after cardiac arrest [CA] (7,814 patients). With moderate certainty on effect estimates, we observed significantly different mortality estimates for various etiologies (p < 0.001), which is not explained by differences in age and sex across studies: 35% (95% CI: 29-42) for after HTx, 40% (95% CI: 33-46) for myocarditis, 53% (95% CI: 46-59) for HF, 52% (95% CI: 38-66) for PE, 59% (95% CI: 56-63) for cardiotomy, 60% (95% CI: 57-64) for AMI, 64% (95% CI: 59-69) for post‒in-hospital CA, and 76% (95% CI: 69-82) for post-out‒of-hospital CA. Univariable metaregression showed that variation in mortality estimates within etiology group was partially explained by population age, proportion of females, left ventricle venting, and CA.

Conclusions: Using an overall estimate of mortality for patients with CS requiring VA ECMO is inadequate given the differential outcomes by etiology. To further refine patient selection and management to improve outcomes, additional studies evaluating patient characteristics impacting outcomes by specific CS etiology are needed.
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http://dx.doi.org/10.1016/j.healun.2021.01.009DOI Listing
April 2021

Successful left ventricular assist device management requires more than a prime pump.

J Card Surg 2021 Mar 2;36(3):1162-1165. Epub 2021 Feb 2.

Ted Rogers Center for Heart Research, Toronto, Canada.

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http://dx.doi.org/10.1111/jocs.15385DOI Listing
March 2021

Predicting Survival After VA-ECMO for Refractory Cardiogenic Shock: Validating the SAVE Score.

CJC Open 2021 Jan 16;3(1):71-81. Epub 2020 Sep 16.

Peter Munk Cardiac Centre, Toronto, Ontario, Canada.

Background: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is used increasingly to support patients who are in cardiogenic shock. Due to the risk of complications, prediction models may aid in identifying patients who would benefit most from VA-ECMO. One such model is the Survival After Veno-Arterial Extracorporeal Membrane Oxygenation (SAVE) score. Therefore, we wanted to validate the utility of the SAVE score in a contemporary cohort of adult patients.

Methods: Retrospective data were extracted from electronic health records of 120 patients with cardiogenic shock supported with VA-ECMO between 2011 and 2018. The SAVE score was calculated for each patient to predict survival to hospital discharge. We assessed the SAVE score calibration by comparing predicted vs observed survival at discharge. We assessed discrimination with the area under the receiver operating curve using logistic regression.

Results: A total of 45% of patients survived to hospital discharge. Survivors had a significantly higher mean SAVE score (-9.3 ± 4.1 in survivors vs -13.1 ± 4.4, respectively;  = 0.001). SAVE score discrimination was adequate (c = 0.77; 95% confidence interval 0.69-0.86; < 0.001). SAVE score calibration was limited, as observed survival rates for risk classes II-V were higher in our cohort (II: 67% vs 58%; III: 78% vs 42%; IV: 61% vs 30%; and V: 29% vs 18%).

Conclusions: The SAVE score underestimates survival in a contemporary North American cohort of adult patients with cardiogenic shock. Its inaccurate performance could lead to denying ECMO support to patients deemed to be too high risk. Further studies are needed to validate additional predictive models for patients requiring VA-ECMO.
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http://dx.doi.org/10.1016/j.cjco.2020.09.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7801193PMC
January 2021

Inhibiting the Pkm2/b-catenin axis drives in vivo replication of adult cardiomyocytes following experimental MI.

Cell Death Differ 2021 Apr 7;28(4):1398-1417. Epub 2020 Dec 7.

Toronto General Research Institute, 100 College St., M5G 1L7, Toronto, ON, Canada.

Adult mammalian cardiomyocytes (CM) are postmitotic, differentiated cells that cannot re-enter the cell cycle after any appreciable injury. Therefore, understanding the factors required to induce CM proliferation for repair is of great clinical importance. While expression of muscle pyruvate kinase 2 (Pkm2), a cytosolic enzyme catalyzing the final step in glycolysis, is high in end-stage heart failure (HF), the loss of Pkm2 promotes proliferation in some cellular systems, in vivo. We hypothesized that in the adult heart CM proliferation may require low Pkm2 activity. Thus, we investigated the potential for Pkm2 to regulate CM proliferation in a mouse model of myocardial infarction (MI) employing inducible, cardiac-specific Pkm2 gene knockout (Pkm2KOi) mice. We found a lack of cardiac hypertrophy or expression of the fetal gene program in Pkm2KOi mice post MI, as compared to vehicle control animals (P < 0.01), correlating with smaller infarct size, improved mitochondrial (mt) function, enhanced angiogenesis, reduced degree of CM apoptosis, and reduced oxidative stress post MI. There was significantly higher numbers of dividing CM in the infarct zone between 3-9 days post MI (P < 0.001). Mechanistically, we determined that Pkm2 interacts with β-catenin (Ctnnb1) in the cytoplasm of CM, inhibiting Ctnnb1 phosphorylation at serine 552 and tyrosine 333, by Akt. In the absence of Pkm2, Ctnnb1 translocates to the nucleus leading to transcriptional activation of proliferation-associated target genes. All these effects are abrogated by genetic co-deletion of Pkm2 and Ctnnb1. Collectively, this work supports a novel antiproliferative function for Pkm2 in CM through the sequestration of Ctnnb1 in the cytoplasm of CM whereas loss of Pkm2 is essential for CM proliferation. Reducing cardiac Pkm2 expression may provide a useful strategy for cardiac repair after MI in patients.
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http://dx.doi.org/10.1038/s41418-020-00669-9DOI Listing
April 2021

Machine learning vs. conventional statistical models for predicting heart failure readmission and mortality.

ESC Heart Fail 2021 Feb 17;8(1):106-115. Epub 2020 Nov 17.

University of Toronto, ICES, Rm G-106, 2075 Bayview Ave., Toronto, ON, M4G2E1, Canada.

Aims: This study aimed to review the performance of machine learning (ML) methods compared with conventional statistical models (CSMs) for predicting readmission and mortality in patients with heart failure (HF) and to present an approach to formally evaluate the quality of studies using ML algorithms for prediction modelling.

Methods And Results: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we performed a systematic literature search using MEDLINE, EPUB, Cochrane CENTRAL, EMBASE, INSPEC, ACM Library, and Web of Science. Eligible studies included primary research articles published between January 2000 and July 2020 comparing ML and CSMs in mortality and readmission prognosis of initially hospitalized HF patients. Data were extracted and analysed by two independent reviewers. A modified CHARMS checklist was developed in consultation with ML and biostatistics experts for quality assessment and was utilized to evaluate studies for risk of bias. Of 4322 articles identified and screened by two independent reviewers, 172 were deemed eligible for a full-text review. The final set comprised 20 articles and 686 842 patients. ML methods included random forests (n = 11), decision trees (n = 5), regression trees (n = 3), support vector machines (n = 9), neural networks (n = 12), and Bayesian techniques (n = 3). CSMs included logistic regression (n = 16), Cox regression (n = 3), or Poisson regression (n = 3). In 15 studies, readmission was examined at multiple time points ranging from 30 to 180 day readmission, with the majority of studies (n = 12) presenting prediction models for 30 day readmission outcomes. Of a total of 21 time-point comparisons, ML-derived c-indices were higher than CSM-derived c-indices in 16 of the 21 comparisons. In seven studies, mortality was examined at 9 time points ranging from in-hospital mortality to 1 year survival; of these nine, seven reported higher c-indices using ML. Two of these seven studies reported survival analyses utilizing random survival forests in their ML prediction models. Both reported higher c-indices when using ML compared with CSMs. A limitation of studies using ML techniques was that the majority were not externally validated, and calibration was rarely assessed. In the only study that was externally validated in a separate dataset, ML was superior to CSMs (c-indices 0.913 vs. 0.835).

Conclusions: ML algorithms had better discrimination than CSMs in most studies aiming to predict risk of readmission and mortality in HF patients. Based on our review, there is a need for external validation of ML-based studies of prediction modelling. We suggest that ML-based studies should also be evaluated using clinical quality standards for prognosis research. Registration: PROSPERO CRD42020134867.
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http://dx.doi.org/10.1002/ehf2.13073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7835549PMC
February 2021

Redo sternotomy versus left ventricular assist device explant as risk factors for early mortality following heart transplantation.

Interact Cardiovasc Thorac Surg 2020 11;31(5):603-610

Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.

Objectives: There is an increasing proportion of patients with a previous sternotomy (PS) or durable left ventricular assist device (LVAD) undergoing heart transplantation (HT). We hypothesized that patients with LVAD support at the time of HT have a lower risk than patients with PS and may have a comparable risk to patients with a virgin chest (VC).

Methods: This is a single-centre retrospective cohort study of all adults who underwent primary single-organ HT between 2002 and 2017. Multivariable Cox regression analyses were performed to compare 30-day and 1-year mortality between transplanted patients with a VC (VC-HT), a PS (PS-HT) or an LVAD explant (LVAD-HT).

Results: Three hundred seventy-nine patients were analysed (VC-HT: 196, PS-HT: 94, LVAD-HT: 89). A larger proportion of patients in the LVAD-HT group were males (83%), had blood group O (52%), non-ischaemic aetiology (70%) and sensitization (67%). The PS-HT group had a higher frequency of patients with congenital heart disease (30%) and PSs compared to LVAD-HT patients (P < 0.001). PS-HT and LVAD-HT patients required a longer bypass time (P < 0.001) and showed a greater estimated blood loss (P < 0.001). Postoperatively, LVAD-HT required haemodialysis more frequently than the VC-HT group (P = 0.031). Multivariable analyses found that PS-HT patients had increased 30-day mortality compared to VC-HT [hazard ratio (HR) 2.63, 95% confidence interval (CI) 1.15-6.01; P = 0.022] while LVAD-HT did not (HR 2.17, 95% CI 0.96-4.93; P = 0.064). At 1-year, neither PS-HT nor LVAD-HT groups were significantly associated with increased mortality compared to VC-HT.

Conclusions: Transplants in recipients with PS-HT demonstrated increased early mortality compared to VC-HT patients. Although LVAD explant is often technically challenging, this population demonstrated similar mortality compared to those VC-HT patients. The chronic and perioperative support provided by the LVAD may play a favourable role in early patient outcomes compared to other redo sternotomy patients.
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http://dx.doi.org/10.1093/icvts/ivaa180DOI Listing
November 2020

Fasting status and metabolic health in relation to plasma branched chain amino acid concentrations in women.

Metabolism 2021 04 15;117:154391. Epub 2020 Oct 15.

Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada; Ted Rogers Centre for Heart Research, University of Toronto, Toronto, ON, Canada; Heart and Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, ON, Canada. Electronic address:

Background: Circulating branched chain amino acids (BCAA) are associated with cardiometabolic risk, although the mechanisms leading to their accumulation remain uncertain. Examining the relationship between fasting status, metabolic syndrome, and type 2 diabetes (T2D) with circulating BCAA levels may provide insights into their metabolic handling.

Methods: We conducted cross-sectional analyses among 25,740 Women's Health Study participants (mean age 55 years).

Results: In multivariable linear regression models, fasting was associated with lower plasma BCAAs vs. non-fasting in women without metabolic syndrome or T2D (% mean difference = -5.1%; 95% CI = -5.8, -4.5) and among women with metabolic syndrome only (-3.7%; -4.9, -2.6), p = 0.002. However, there was no difference in BCAAs by fasting status among women with T2D (0.4%; -3.7, 4.7).

Conclusions: We observed higher BCAAs with worsening metabolic health status. Fasting is modestly associated with lower plasma BCAAs, except among women with T2D. These findings support hypotheses that impaired BCAA catabolism may be a feature of T2D pathophysiology.
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http://dx.doi.org/10.1016/j.metabol.2020.154391DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985990PMC
April 2021

Predicting the Risk of Right Ventricular Failure in Patients Undergoing Left Ventricular Assist Device Implantation: A Systematic Review.

Circ Heart Fail 2020 10 28;13(10):e006994. Epub 2020 Sep 28.

Heart Failure and Transplant Program, Peter Munk Cardiac Centre (M.M., J.K.K.V.-N., F.F., F.B., A.C.A.), University Health Network, Toronto, Canada.

Background: Right ventricular failure (RVF) is a cause of major morbidity and mortality after left ventricular assist device (LVAD) implantation. It is, therefore, integral to identify patients who may benefit from biventricular support early post-LVAD implantation. Our objective was to explore the performance of risk prediction models for RVF in adult patients undergoing LVAD implantation.

Methods: A systematic search was performed on Medline, Embase, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews from inception until August 2019 for all relevant studies. Performance was assessed by discrimination (via C statistic) and calibration if reported. Study quality was assessed using the Prediction Model Risk of Bias Assessment Tool criteria.

Results: After reviewing 3878 citations, 25 studies were included, featuring 20 distinctly derived models. Five models were derived from large multicenter cohorts: the European Registry for Patients With Mechanical Circulatory Support, Interagency Registry for Mechanically Assisted Circulatory Support, Kormos, Pittsburgh Bayesian, and Mechanical Circulatory Support Research Network RVF models. Seventeen studies (68%) were conducted in cohorts implanted with continuous-flow LVADs exclusively. The definition of RVF as an outcome was heterogenous among models. Seven derived models (28%) were validated in at least 2 cohorts, reporting limited discrimination (C-statistic range, 0.53-0.65). Calibration was reported in only 3 studies and was variable.

Conclusions: Existing RVF prediction models exhibit heterogeneous derivation and validation methodologies, varying definitions of RVF, and are mostly derived from single centers. Validation studies of these prediction models demonstrate poor-to-modest discrimination. Newer models are derived in cohorts implanted with continuous-flow LVADs exclusively and exhibit modest discrimination. Derivation of enhanced discriminatory models and their validations in multicenter cohorts is needed.
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http://dx.doi.org/10.1161/CIRCHEARTFAILURE.120.006994DOI Listing
October 2020

Haploinsufficiency of RREB1 causes a Noonan-like RASopathy via epigenetic reprogramming of RAS-MAPK pathway genes.

Nat Commun 2020 09 16;11(1):4673. Epub 2020 Sep 16.

Princess Margaret Cancer Centre, University Health Network, 101 College Street, Toronto, ON, M5G 1×5, Canada.

RAS-MAPK signaling mediates processes critical to normal development including cell proliferation, survival, and differentiation. Germline mutation of RAS-MAPK genes lead to the Noonan-spectrum of syndromes. Here, we present a patient affected by a 6p-interstitial microdeletion with unknown underlying molecular etiology. Examination of 6p-interstitial microdeletion cases reveals shared clinical features consistent with Noonan-spectrum disorders including short stature, facial dysmorphia and cardiovascular abnormalities. We find the RAS-responsive element binding protein-1 (RREB1) is the common deleted gene in multiple 6p-interstitial microdeletion cases. Rreb1 hemizygous mice display orbital hypertelorism and cardiac hypertrophy phenocopying the human syndrome. Rreb1 haploinsufficiency leads to sensitization of MAPK signaling. Rreb1 recruits Sin3a and Kdm1a to control H3K4 methylation at MAPK pathway gene promoters. Haploinsufficiency of SIN3A and mutations in KDM1A cause syndromes similar to RREB1 haploinsufficiency suggesting genetic perturbation of the RREB1-SIN3A-KDM1A complex represents a new category of RASopathy-like syndromes arising through epigenetic reprogramming of MAPK pathway genes.
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http://dx.doi.org/10.1038/s41467-020-18483-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7495420PMC
September 2020

Management of Acute Decompensated Heart Failure in the Cardiac Intensive Care Unit: The Importance of Co-management With a Heart Failure Specialist.

CJC Open 2020 Jul 4;2(4):229-235. Epub 2020 Mar 4.

Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada.

Background: Heart failure (HF) is a common reason for admission to the cardiac intensive care unit. We sought to identify the role of an HF consultation service in improving the management of this patient population.

Methods: We identified all adult patients admitted to the cardiac intensive care unit (2014-2015) at the University Health Network with a diagnosis of acute decompensated HF ± cardiogenic shock (CS). Clinical characteristics and course were recorded. We calculated a propensity score-adjusted association between HF consultation and in-hospital mortality.

Results: A total of 285 unique patients were identified in our cohort. Of these, 82 (28.7%) died. A total of 150 patients (52.6%) were co-managed by an HF service, and 135 patients (47.3%) were not. Patients who were managed by an HF team were younger (52.5 vs 68.0 years, 0.0001), were more likely to be admitted with CS (61.3 vs 41.5%, 0.0009), and had higher rates of vasoactive medications during their admission (69.3% vs 52.6%, 0.005). At discharge, there were higher rates of discharge to a HF clinic (52.0% vs 27.5%, 0.0001) and prescription of guideline-directed medical therapy. In-hospital mortality was lower in those co-managed by a HF team (16.7% vs 42.2%, 0.0001). HF consultation reduced the odds of readmission by 76% (odds ratio, 0.24; 95% confidence interval, 0.13-0.47).

Conclusions: Patients managed by a HF team were more likely to be in CS at admission, to survive to discharge from hospital, and to be initiated on guideline-directed medical therapy with HF follow-up.
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http://dx.doi.org/10.1016/j.cjco.2020.02.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365826PMC
July 2020

Anthracycline-induced cardiomyopathy: cellular and molecular mechanisms.

Clin Sci (Lond) 2020 07;134(13):1859-1885

Toronto General Hospital Research Institute, 101 College St., Toronto, Canada.

Despite the known risk of cardiotoxicity, anthracyclines are widely prescribed chemotherapeutic agents. They are broadly characterized as being a robust effector of cellular apoptosis in rapidly proliferating cells through its actions in the nucleus and formation of reactive oxygen species (ROS). And, despite the early use of dexrazoxane, no effective treatment strategy has emerged to prevent the development of cardiomyopathy, despite decades of study, suggesting that much more insight into the underlying mechanism of the development of cardiomyopathy is needed. In this review, we detail the specific intracellular activities of anthracyclines, from the cell membrane to the sarcoplasmic reticulum, and highlight potential therapeutic windows that represent the forefront of research into the underlying causes of anthracycline-induced cardiomyopathy.
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http://dx.doi.org/10.1042/CS20190653DOI Listing
July 2020

Mapping signalling perturbations in myocardial fibrosis via the integrative phosphoproteomic profiling of tissue from diverse sources.

Nat Biomed Eng 2020 09 13;4(9):889-900. Epub 2020 Jul 13.

Department of Biology, Boston University, Boston, MA, USA.

Study of the molecular basis of myocardial fibrosis is hampered by limited access to tissues from human patients and by confounding variables associated with sample accessibility, collection, processing and storage. Here, we report an integrative strategy based on mass spectrometry for the phosphoproteomic profiling of normal and fibrotic cardiac tissue obtained from surgical explants from patients with hypertrophic cardiomyopathy, from a transaortic-constriction mouse model of cardiac hypertrophy and fibrosis, and from a heart-on-a-chip model of cardiac fibrosis. We used the integrative approach to map the relative abundance of thousands of proteins, phosphoproteins and phosphorylation sites specific to each tissue source, to identify key signalling pathways driving fibrosis and to screen for anti-fibrotic compounds targeting glycogen synthase kinase 3, which has a consistent role as a key mediator of fibrosis in all three types of tissue specimen. The integrative disease-modelling strategy may reveal new insights into mechanisms of cardiac disease and serve as a test bed for drug screening.
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http://dx.doi.org/10.1038/s41551-020-0585-yDOI Listing
September 2020

The changing landscape of left ventricular assist device care in the setting of a pandemic.

ESC Heart Fail 2020 10 7;7(5):2140-2142. Epub 2020 Jul 7.

Peter Munk Cardiac Center, Division of Cardiology, University Health Network, Toronto, ON, M5G 2N2, Canada.

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http://dx.doi.org/10.1002/ehf2.12845DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362049PMC
October 2020

The Effect of Age on Outcomes After Destination-Therapy Left Ventricular Assist Device Implantation: An Analysis of the IMACS Registry.

Can J Cardiol 2021 Mar 22;37(3):467-475. Epub 2020 Jun 22.

Peter Munk Cardiac Centre, Toronto General Hospital-University Health Network, Toronto, Ontario, Canada. Electronic address:

Background: As patients with advanced heart failure are living longer, defining the impact of left ventricular assist devices (LVADs) on outcomes in an aging population is of great importance. We describe overall survival, rates of adverse events (AEs), and post-AE survival in patients age ≥ 70 years vs age 50-69 years after destination-therapy (DT) LVAD implantation.

Methods: A retrospective analysis was conducted with the use of the International Society for Heart and Lung Transplantation Mechanically Assisted Circulatory Support (IMACS) registry. All adults age ≥ 50 years with a continuous-flow DT LVAD from 2013 to 2017 were included. The primary outcome was all-cause mortality. The secondary outcomes were the incidence of and survival after gastrointestinal (GI) bleeding, infection, stroke, pump thrombosis, pump exchange, and right-side heart failure. Mortality and AEs were assessed with the use of competing risk models.

Results: At total of 5,572 patients were included: 3,700 aged 50-69 and 1,872 aged ≥ 70. All-cause mortality by 42 months was 55.8% in patients aged ≥ 70 and 44.8% in patients aged 50-69 (P = 0.001). Patients aged ≥ 70 had a 37.8% higher risk of death after DT LVAD implantation (hazard ratio 1.378, 95% CI 1.251-1.517). Patients aged ≥ 70 had higher risk of GI bleeding but lower risk of right-side heart failure. There was no difference between age groups for risk of infection or stroke. Experiencing any AE was associated with an increased risk of death that did not vary with age.

Conclusions: Patients aged ≥ 70 years have reduced survival after DT LVAD, in part because of increased GI bleeding, while the incidence of other AEs is similar to that of patients aged 50-69 years. Careful patient selection beyond age alone may allow for optimal outcomes after DT LVAD implantation.
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http://dx.doi.org/10.1016/j.cjca.2020.06.010DOI Listing
March 2021

Cardiovascular Collapse in COVID-19 Infection: The Role of Venoarterial Extracorporeal Membrane Oxygenation (VA-ECMO).

CJC Open 2020 Jul 8;2(4):273-277. Epub 2020 Apr 8.

Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.

Coronavirus Disease 2019 (COVID-19) has been associated with cardiovascular complications, including acute cardiac injury, heart failure, and cardiogenic shock (CS). The role of venoarterial extracorporeal membrane oxygenation (VA-ECMO) in the event of COVID-19-associated cardiovascular collapse has not been established. We reviewed the existing literature surrounding the role of VA-ECMO in the treatment of coronavirus-related cardiovascular collapse. COVID-19 is associated with a higher incidence of cardiovascular complications compared with previous coronavirus outbreaks (Severe Acute Respiratory Syndrome Coronavirus and Middle East Respiratory Syndrome Coronavirus). We found only 1 case report from China in which COVID-19-associated fulminant myocarditis and CS were successfully rescued using VA-ECMO as a bridge to recovery. We identified potential clinical scenarios (cardiac injury, myocardial infarction with and without obstructive coronary artery disease, viral myocarditis, and decompensated heart failure) leading to CS and risk factors for poor/uncertain benefit (age, sepsis, mixed/predominantly vasodilatory shock, prothrombotic state or coagulopathy, severe acute respiratory distress syndrome, multiorgan failure, or high-risk prognostic scores) specific to using VA-ECMO as a bridge to recovery in COVID-19 infection. Additional considerations and proposed recommendations specific to the COVID-19 pandemic were formulated with guidance from published data and expert consensus. A small subset of patients with cardiovascular complications from COVID-19 infection may progress to refractory CS. While accepting that resource scarcity may be the overwhelming concern for healthcare systems during this pandemic, VA-ECMO can be considered in highly selected cases of refractory CS and echocardiographic evidence of biventricular failure. The decision to initiate this therapy should take into consideration the availability of resources, perceived benefit, and risks of transmitting disease.
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http://dx.doi.org/10.1016/j.cjco.2020.04.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7194983PMC
July 2020

REEP5 depletion causes sarco-endoplasmic reticulum vacuolization and cardiac functional defects.

Nat Commun 2020 02 19;11(1):965. Epub 2020 Feb 19.

Translational Biology and Engineering Program, Ted Rogers Centre for Heart Research, Toronto, ON, M5G1M1, Canada.

The sarco-endoplasmic reticulum (SR/ER) plays an important role in the development and progression of many heart diseases. However, many aspects of its structural organization remain largely unknown, particularly in cells with a highly differentiated SR/ER network. Here, we report a cardiac enriched, SR/ER membrane protein, REEP5 that is centrally involved in regulating SR/ER organization and cellular stress responses in cardiac myocytes. In vitro REEP5 depletion in mouse cardiac myocytes results in SR/ER membrane destabilization and luminal vacuolization along with decreased myocyte contractility and disrupted Ca cycling. Further, in vivo CRISPR/Cas9-mediated REEP5 loss-of-function zebrafish mutants show sensitized cardiac dysfunction upon short-term verapamil treatment. Additionally, in vivo adeno-associated viral (AAV9)-induced REEP5 depletion in the mouse demonstrates cardiac dysfunction. These results demonstrate the critical role of REEP5 in SR/ER organization and function as well as normal heart function and development.
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http://dx.doi.org/10.1038/s41467-019-14143-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7031342PMC
February 2020

Excessive Left Ventricular Trabeculation: New Evidence Points to Pathological Significance in a Previously Murky Area.

Can J Cardiol 2020 04 1;36(4):462-463. Epub 2019 Nov 1.

Peter Munk Cardiac Centre, Toronto General Hospital-University Health Network, Toronto, Ontario, Canada. Electronic address:

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http://dx.doi.org/10.1016/j.cjca.2019.10.026DOI Listing
April 2020

Utility of the INTERMACS profile at the time of assessment for heart transplant.

Clin Transplant 2020 03 17;34(3):e13796. Epub 2020 Feb 17.

Ted Rogers Centre for Heart Research, Multi-Organ Transplant Program, Toronto General Hospital, University Health Network, Toronto, ON, Canada.

The Interagency Registry of Mechanically Assisted Circulatory Support (INTERMACS) profiles are associated with mortality in heart failure patients undergoing ventricular assist device (VAD) implantation and heart transplantation (HTx). We assessed the prognostic value of the INTERMACS profile at the time of assessment for HTx or durable VAD implantation as bridge to candidacy (BTC). A total of 503 consecutive patients considered for HTx or VAD between 2006 and 2016 were included. The associations between INTERMACS profile and (a) waitlist mortality or delisting, (b) probability of HTx, and (c) overall mortality or delisting were evaluated using multivariable analysis. Median follow-up time was 2.9 years (IQR: 0.9-5.5) during which 184 received VAD, 347 received HTx, and 73 died (27 waitlist, 46 post-transplant). INTERMACS I-II profile was associated with higher waitlist mortality or delisting (HR: 3.83, 95% CI: 1.22-12.03), and this risk was reversed by VAD implantation (HR: 0.12, 95% CI: 0.03-0.50). INTERMACS III-IV profile was associated with a higher probability of HTx (HR: 1.82, 95% CI: 1.37-2.40). INTERMACS profile was not associated with the composite outcome of overall mortality or delisting. These results emphasize the prognostic utility of INTERMACS at time of decision for advanced therapies and its potential value in selecting patients for different interventions.
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http://dx.doi.org/10.1111/ctr.13796DOI Listing
March 2020

Heart Failure: A Palliative Medicine Review of Disease, Therapies, and Medications With a Focus on Symptoms, Function, and Quality of Life.

J Pain Symptom Manage 2020 05 19;59(5):1127-1146.e1. Epub 2019 Dec 19.

Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada; Division of Palliative Care, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Despite significant advances in heart failure (HF) treatment, HF remains a progressive, extremely symptomatic, and terminal disease with a median survival of 2.1 years after diagnosis. HF often leads to a constellation of symptoms, including dyspnea, fatigue, depression, anxiety, insomnia, pain, and worsened cognitive function. Palliative care is an approach that improves the quality of life of patients and their caregivers facing the problems associated with life-threatening illness and therefore is well suited to support these patients. However, historically, palliative care has often focused on supporting patients with malignant disease, rather than a progressive chronic disease such as HF. Predicting mortality in patients with HF is challenging. The lack of obvious transition points in disease progression also raises challenges to primary care providers and specialists to know at what point to integrate palliative care during a patient's disease trajectory. Although therapies for HF often result in functional and symptomatic improvements including health-related quality of life (HRQL), some patients with HF do not demonstrate these benefits, including those patients with a preserved ejection fraction. Provision of palliative care for patients with HF requires an understanding of HF pathogenesis and common medications used for these patients, as well as an approach to balancing life-prolonging and HRQL care strategies. This review describes HF and current targeted therapies and their effects on symptoms, hospital admission rates, exercise performance, HRQL, and survival. Pharmacological interactions with and precautions related to commonly used palliative care medications are reviewed. The goal of this review is to equip palliative care clinicians with information to make evidence-based decisions while managing the balance between optimal disease management and patient quality of life.
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http://dx.doi.org/10.1016/j.jpainsymman.2019.12.357DOI Listing
May 2020

Protective role of Nrf2 against ischemia reperfusion injury and cardiac allograft vasculopathy.

Am J Transplant 2020 05 3;20(5):1262-1271. Epub 2020 Jan 3.

Division of Cardiovascular Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Ischemia-reperfusion injury (IRI) and cardiac allograft vasculopathy (CAV) remain unsolved complications post-heart transplant (Tx). The antioxidant transcription factor Nuclear factor erythroid 2-related factor 2 (Nrf2) has been suggested to inhibit reactive oxygen species-mediated NF-κB activation. We hypothesized that Nrf2 inhibits NF-κB activation post-Tx and suppresses IRI and the subsequent development of CAV. IRI and CAV were investigated in murine heterotopic Tx models, respectively. Nrf2 wild-type (WT) and KO mice were used as donors. Sulforaphane was used as an Nrf2 agonist. In saline-treated animals following 24 hours of reperfusion in isogenic grafts, Nrf2-KO showed significantly less SOD1/2 activity compared with WT. Nrf2-KO displayed significantly high total and phosphorylated p65 expressions and percentage of cells with nuclear p65. mRNA levels of NF-κB-mediated proinflammatory genes were also high. Graft dysfunction, apoptosis, and caspase-3 activity were significantly higher in Nrf2-KO. In the allograft studies, graft beating score was significantly weaker in Nrf2-KO compared with WT. Nrf2-KO also demonstrated significantly more coronary luminal narrowing. In WT animals, sulforaphane successfully augmented all the protective effects of Nrf2 with increase of SOD2 activity. Nrf2 inhibits NF-κB activation and protects against IRI via its antioxidant properties and suppresses the subsequent development of CAV.
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http://dx.doi.org/10.1111/ajt.15724DOI Listing
May 2020

Neurohormones, inflammatory mediators, and cardiovascular injury in the setting of heart failure.

Heart Fail Rev 2020 09;25(5):685-701

Division of Nephrology, University Health Network, University of Toronto, Toronto, ON, M5S, Canada.

Neurohormones and inflammatory mediators have effects in both the heart and the peripheral vasculature. In patients with heart failure (HF), neurohormonal activation and increased levels of inflammatory mediators promote ventricular remodeling and development of HF, as well as vascular dysfunction and arterial stiffness. These processes may lead to a vicious cycle, whereby arterial stiffness perpetuates further ventricular remodeling leading to exacerbation of symptoms. Although significant advances have been made in the treatment of HF, currently available treatment strategies slow, but do not halt, this cycle. The current treatment for HF patients involves the inhibition of neurohormonal activation, which can reduce morbidity and mortality related to this condition. Beyond benefits associated with neurohormonal blockade, other strategies have focused on inhibition of inflammatory pathways implicated in the pathogenesis of HF. Unfortunately, attempts to target inflammation have not yet been successful to improve prognosis of HF. Further work is required to interrupt key maladaptive mechanisms involved in disease progression.
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http://dx.doi.org/10.1007/s10741-019-09860-8DOI Listing
September 2020

Hemodynamic Aspects of Veno-Arterial Extracorporeal Membrane Oxygenation for Cardiac Support: A Worldwide Survey.

ASAIO J 2020 05;66(5):489-496

From the Peter Munk Cardiac Centre, Division of Cardiology, University Health Network, Toronto, Ontario, Canada.

There is limited data available to guide management of patients supported with veno-arterial extracorporeal membrane oxygenation (VA-ECMO). An international cross-sectional survey of medical directors/program coordinators from Extracorporeal Life Support Organization centers was conducted. A hierarchical clustering on principle components was used. A total of 243 (55%) centers responded and were divided into three clusters: Cluster 1 (n = 102) had few high volumes and low specialized heart failure (HF) involvement; Cluster 2 (n = 75) had few high volumes and moderate HF involvement; Cluster 3 (n = 66) contained the majority of centers with >50 annual cases and high HF involvement. The most divergent responses were observed between Clusters 1 and 3 wherein Cluster 1 centers were less likely to change management based on pulse pressure (77% vs. 100%; p < 0.001) and would rather avoid inotropes to "rest the heart" (28%). Cluster 3 centers were more likely to perform daily echocardiograms (50% vs. 24%, p < 0.001), which were less likely to be exclusively performed by cardiologist (36% vs. 58%, p < 0.046) and base weaning on echocardiographic findings, when compared to Cluster 1 (3.97/5 vs. 3.56, p < 0.001). Responses were variable in management reflecting the lack of evidence for hemodynamic care for those supported with VA-ECMO.
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http://dx.doi.org/10.1097/MAT.0000000000001024DOI Listing
May 2020

Ventricular Standstill in a Patient With a Left Ventricular Assist Device.

Ann Thorac Surg 2019 09 7;108(3):e153-e155. Epub 2019 Mar 7.

Mechanical Circulatory Support Program, Peter Munk Cardiac Centre, Toronto General Hospital, Toronto, Canada; Division of Cardiovascular Surgery, University Health Network, University of Toronto, Toronto, Canada. Electronic address:

A 58-year-old woman had medically refractory heart failure due to idiopathic dilated cardiomyopathy. She underwent tricuspid repair and left ventricular assist device implantation for inotropic-dependent heart failure. Because of severe right ventricular dysfunction, she experienced progressive bradycardia and ventricular asystole with electrocardiographic and echocardiographic standstill. Despite the lack of native cardiac activity, she maintained end-organ perfusion with inotropic support until she underwent successful transplantation. This report highlights a case of mechanical circulatory support with an isolated left ventricular assist device implantation even in the absence of native right ventricular function.
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http://dx.doi.org/10.1016/j.athoracsur.2019.01.066DOI Listing
September 2019

Cardioprotective Effect of Statins in Patients With HER2-Positive Breast Cancer Receiving Trastuzumab Therapy.

Can J Cardiol 2019 02 4;35(2):153-159. Epub 2018 Dec 4.

Division of Cardiology, Peter Munk Cardiac Center, Ted Rogers Program in Cardiotoxicity Prevention, Toronto General Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Statins can reduce the risk of anthracycline-induced cardiotoxicity. Whether such cardioprotective effects can be seen in trastuzumab-treated patients has not been explored.

Methods: Consecutive women with HER2+ breast cancer who received trastuzumab with or without anthracyclines were identified retrospectively. Patients receiving statins before and during cancer treatment were matched with 2 patients of the same age (± 2 years) and anthracycline exposure status but without statin treatment. The primary outcome was final left ventricular ejection fraction (LVEF). Analysis of covariance (ANCOVA) was used to assess the relationship between statin exposure and the final LVEF. A logistic regression model was constructed to assess the relationship between statin exposure and cardiotoxicity (secondary outcome).

Results: Included were 129 patients (62 ± 9 years). Forty-three received statins during cancer treatment. The median trastuzumab exposure time was 11.8 (interquartile range [IQR] 11 to 12) months. Seventy-two (56%) patients received anthracyclines. Compared with controls, patients treated with statins were more likely to have diabetes (37.2% vs 4.7%, P < 0.001), hypertension (58.1% vs 22.1%, P < 0.001), and coronary artery disease (11.6% vs 2.3%, P = 0.04). Within a median cardiac follow-up duration of 11 (IQR 9 to 18) months, the adjusted final LVEF was lower in the control group (61.2% vs 64.6%, P = 0.034). A significant change in LVEF was observed in the control group (median -6%, IQR -10% to -1% P < 0.001) but not in the statin group (median 0%, IQR -5% to +3%, P = 0.27). Upon adjusted analysis, statin treatment was independently associated with a lower risk of cardiotoxicity (odds ratio [OR] 0.32, 95% confidence interval [CI], 0.10-0.99, P = 0.049).

Conclusions: In women with HER2+ breast cancer receiving trastuzumab-based therapy with or without anthracyclines, concomitant use of statins was associated with a lower risk of cardiotoxicity.
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http://dx.doi.org/10.1016/j.cjca.2018.11.028DOI Listing
February 2019

B-Cell Deficiency Lowers Blood Pressure in Mice.

Hypertension 2019 03;73(3):561-570

From the Toronto General Hospital Research Institute, University Health Network, Canada (L.S.D., E.A.S., A.M., T.A., F.B., M.H.).

The proto-oncogene c-myb (and corresponding nuclear transcription factor, c-Myb) regulates the proliferation and differentiation of hematologic and vascular smooth muscle cells; however, the role of c-Myb in blood pressure regulation is unknown. Here, we show that mice homozygous for a hypomorphic c-myb allele ( c-myb ) conferring reduced c-Myb activity manifest reduced peripheral blood and kidney B220 B-cells and have decreased systolic (104±2 versus 120±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 83±1 mm Hg; P<0.0001) compared with WT (wild type) mice. Additionally, c-myb mice had lower susceptibility to deoxycorticosterone acetate-salt experimental hypertension. Although cardiac (echocardiography) and resistance artery (perfusion myography) functions were normal, metabolic cage studies revealed that c-myb mice had increased 24-hour urine output and sodium excretion versus WT. Reconstitution of WT mice with c-myb bone marrow transplant and chimeric bone marrow transplant using mice lacking B-cells ( J T; h/h>WT and h/h:J T>WT, respectively) decreased blood pressure and increased 24-hour urine output compared with controls ( WT>WT; WT:J T>WT). J T mice also had decreased systolic (103±2 versus 115±1 mm Hg; P<0.0001) and diastolic blood pressure (71±2 versus 79±1; P<0.01) and increased 24-hour urine output versus WT. Real-time quantitative reverse transcription polymerase chain reaction of kidney medulla revealed reduced VR (vasopressin receptor 2) expression in c-myb and J T mice. These data implicate B-cells in the regulation of VR and its associated effects on salt and water handling and blood pressure homeostasis.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.118.11828DOI Listing
March 2019

Increases in Serum Autoantibodies After Left Ventricular Assist Device Implantation.

J Card Fail 2019 Apr 7;25(4):301-306. Epub 2019 Jan 7.

Multi-Organ Transplant Program, University Health Network, University of Toronto, Toronto, Canada. Electronic address:

Background: Left ventricular assist devices (LVADs) can serve as a bridge to transplant or destination therapy for patients with advanced heart failure. Implantation of LVADs is known to be associated with increases in anti-HLA antibodies, but less is known about how autoantibody levels change with the use of these devices.

Methods And Results: Autoantibody levels were quantified with the use of customized antigen microarrays in 22 patients both before and after LVAD. We observed an increase (1.5- to 2-fold) in 14 IgG autoantibodies in the serum of patients after LVAD, including autoantibodies against cardiac proteins (myosin, troponin I, tropomyosin), DNA, and structural proteins (collagen, laminin). There was also a small but significant rise in total serum IgG after LVAD. Increases in autoantibodies after LVAD were positively associated with increases in calculated panel-reactive antibody class II (P = .05) and negatively correlated with age (r = -0.45; P < .05). Cytokines were evaluated to gain insights into the mechanism of antibody generation, and we observed a positive correlation between total IgG levels after LVAD and the level of monocyte chemoattractant protein 1 (r = 0.60; P < .05).

Conclusions: LVAD implantation is associated with increases in IgG autoantibodies, anti-HLA antibodies, and total IgG. Increases in IgG after LVAD implantation may relate to an inflammatory response triggered by these devices.
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http://dx.doi.org/10.1016/j.cardfail.2019.01.002DOI Listing
April 2019

Right ventricular fibrosis is associated with cardiac remodelling after pulmonary valve replacement.

Heart 2019 06 4;105(11):855-863. Epub 2018 Dec 4.

Toronto Congenital Cardiac Centre for Adults, Peter Munk Cardiac Centre, University of Toronto, Toronto General Hospital, Toronto, Ontario, Canada.

Objective: The relationship between right ventricular (RV) fibrosis and right heart reverse remodelling following pulmonary valve replacement (PVR) has not been well studied in adults with repaired tetralogy of Fallot (rTOF). Our aims were to histologically quantify RV fibrosis and to explore the relationship between fibrosis severity and cardiac remodelling post-PVR.

Methods: Adults with rTOF and pre-PVR cardiovascular (CMR) imaging were consented to procurement of RV muscle during PVR. Samples were stained with picrosirius red to quantify collagen volume fraction. Clinical data at baseline and at last follow-up were reviewed. Adverse cardiovascular outcomes included death, sustained arrhythmia and heart failure.

Results: Fifty-three patients (male 58%, 38±11 years) were studied. Those with severe fibrosis (collagen volume fraction >11.0%, n=13) had longer aortic cross-clamp times at initial repair compared with the remainder of the population (50 vs 33 min, p=0.018) and increased RV mass:volume ratio pre-PVR (0.20 vs 0.18 g/mL, p=0.028). Post-PVR, the severe fibrosis group had increased indexed RV end-systolic volume index (RVESVi) (74 vs 66 mL/m, p=0.044), decreased RVESVi change (Δ29 vs Δ45 mL/m, p=0.005), increased RV mass (34 vs 25 g/m, p=0.023) and larger right atrial (RA) area (21 vs 17 cm, p=0.021). A trend towards increased heart failure events was observed in the severe fibrosis group (15% vs 0%, p=0.057).

Conclusions: Severe RV fibrosis was associated with increased RVESVi, RV mass and RA area post-PVR in rTOF. Further study is required to define the impact of fibrosis and persistent right heart enlargement on clinical outcomes.
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http://dx.doi.org/10.1136/heartjnl-2018-313961DOI Listing
June 2019