Publications by authors named "Jagdish Butany"

229 Publications

Valve-in-valve prosthesis-late morphological findings.

Cardiovasc Pathol 2021 Sep-Oct;54:107345. Epub 2021 May 12.

University of Toronto, Departments of Laboratory Medicine & Pathobiology & Departments of Pathology & Cardiovascular Surgery, Toronto General Hospital, University Health Network, Toronto, Canada.

Since its implantation in 2002, transcatheter aortic valve implantation (TAVI) has become the preferred intervention for patients with severe aortic stenosis and significant co-morbidities. In 2007, it was adopted as a rescue procedure for failed bioprosthetic valves, now known as the valve-in-valve (VIV) procedure. Unlike other modes of treatment with a multitude of phase 4 post-marketing surveillance (PMS) data, use of these valves have increased rapidly even without long term durability data on this procedure and the near lack of information on the pathology of failed transcatheter aortic valve replacement (TAVR) bioprosthesis and especially after the VIV procedure. We present a case of a late explanted VIV bioprosthesis (ten (10) years post-initial aortic valve replacement and five (5) years post-VIV procedure) in a 65-year-old male with multiple morphologic findings. Further availability of standardized morphologic data from explanted bioprosthetic valves is essential to aid in understanding the pathophysiology of tissue degeneration of the TAVI valve, and ultimately to improve patient outcomes by identifying possible early interventional strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carpath.2021.107345DOI Listing
May 2021

Biomechanics of Aortic Dissection: A Comparison of Aortas Associated With Bicuspid and Tricuspid Aortic Valves.

J Am Heart Assoc 2020 08 28;9(15):e016715. Epub 2020 Jul 28.

Division of Cardiovascular Surgery University Health Network Toronto ON Canada.

Background Current methods for aortic dissection risk assessment are inadequate for patients with ascending aortic aneurysms associated with either bicuspid aortic valves (BAVs) or tricuspid aortic valves (TAVs). Biomechanical testing of aortic tissue may provide novel insights and biomarkers. Methods and Results From March 2017 to August 2019, aneurysmal ascending aortas (BAV=23, TAV=23) were collected from elective aortic surgery, normal aortas from transplant donors (n=9), and dissected aortas from surgery for aortic dissection (n=7). These aortas underwent delamination testing in simulation of aortic dissection. Biaxial tensile testing was performed to determine modulus of elasticity (aortic stiffness), and energy loss (a measure of efficiency in performing the Windkessel function). Delamination strength () was lowest in dissected aortas (18±6 mN/mm) and highest in normal aortas (58±16 mN/mm), and aneurysms fell in between, with greater in the BAV group (37±10 mN/mm) than the TAV group (27±10 mN/mm) (<0.001). Bicuspid aortopathy was associated with greater stiffness (<0.001), while aneurysms with TAV demonstrated greater energy loss (<0.001). decreased by 7.8±1.2 mmol/L per mm per decade of life (=0.45, <0.001), and it was significantly lower for patients with hypertension (=0.001). decreased by 6.1±2.1 mmol/L per mm with each centimeter increase in aortic diameter (=0.15, =0.007). Increased energy loss was associated with decreased (=0.41), whereas there was no relationship between and aortic stiffness. Conclusions Aneurysms with BAV had higher than those with TAV, suggesting that BAV was protective. Energy loss was lower in aneurysms with BAV, and inversely associated with , representing a potential novel biomarker.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/JAHA.120.016715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792273PMC
August 2020

A calcified chronic total occlusion preclinical model.

Catheter Cardiovasc Interv 2021 02 3;97(3):437-442. Epub 2020 Apr 3.

Schulich Heart Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada.

Objective: To create an experimental chronic total occlusion (CTO) model with calcification by dietary modification (cholesterol, calcium carbonate, vitamin D) and local injection of pro-calcification factors (dipotassium phosphate, calcium chloride, and bone morphogenetic protein-2 [BMP-2]).

Background: Percutaneous revascularization of CTOs frequently fails in heavily calcified occlusions. Development of novel approaches requires a reproducible preclinical model of calcified CTO.

Methods: CTOs were created in 18 femoral arteries of 9 New Zealand White rabbits using the thrombin injection model. Dietary interventions included a high cholesterol diet (0.5% or 0.25%), calcium carbonate (150 mg × 3-5 days/week), and vitamin D (50,000 U × 3-5 days/week). In selected animals, BMP-2 (1-4 μg), dipotassium phosphate, and calcium chloride were injected locally at the time of CTO creation. Animals were sacrificed at 2 weeks (n = 4 arteries), 6 weeks (n = 4 arteries), and 10-12 weeks (n = 14 arteries).

Results: CTOs showed evidence of chronic lipid feeding (foam cells) and chronic inflammation (intimal/medial fibrosis and microvessels, inflammatory cells, internal elastic lamina disruption). In calcium/vitamin D supplemented rabbits, mineralization (calcification and/or ossification) was evident as early as 2 weeks post CTO creation, and in 78% of the overall arteries. Mineralization changes were not present in the absence of calcium/vitamin D dietary supplements. Mineralization occurred in 85% of BMP-treated arteries and 60% of arteries without BMP.

Conclusions: Complex mineralization occurs in preclinical CTO models with dietary supplementation of cholesterol with vitamin D and calcium.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ccd.28870DOI Listing
February 2021

Lipomatous hypertrophy of the interatrial septum is a pathologic, not an anatomic diagnosis.

J Card Surg 2020 May 1;35(5):1132-1134. Epub 2020 Apr 1.

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

Background And Aim: Lipomatous hypertrophy of the interatrial septum (LHIS), a fatty tumor, is usually diagnosed on both echo and CT/MRI imaging. Cases of LHIS located outside of the interatrial septum are extremely rare and rarer still are these cases large enough to cause symptoms. The clinical literature demonstrates a misunderstanding that fatty tumors outside the intra-atrial area represent lipomas. However, pathologic understanding of these fatty tumors is clear and is based on microscopic findings.

Methods: The tumor was removed by diving the base of attachment at the left ventricular apex via a median sternotomy on cardiopulmonary bypass.

Results: The patient made an uneventful recovery and remains well at 6 months postoperatively.

Conclusions: On rare occasions, LHIS can arise from outside the interatrial septum. An LHIS can be differentiated from a lipoma by the presence of entrapped cardiac myocytes in LHIS, making it a pathological, rather than an anatomic, diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jocs.14528DOI Listing
May 2020

Modes of bioprosthetic valve failure: a narrative review.

Curr Opin Cardiol 2020 03;35(2):123-132

Toronto General Hospital, Toronto, Ontario, Canada.

Purpose Of Review: A thorough understanding of the modes of bioprosthetic valve failure is critical as clinicians will be facing an increasing number of patients presenting with failed bioprostheses in coming years. The purpose of this article is to review modes of bioprosthestic valve degeneration, their management, and identify gaps for future research.

Recent Findings: Guidelines recommend monitoring hemodynamic performance of prosthetic valves using serial echocardiograms to determine valve function and presence of valve degeneration. Modes of bioprosthetic valve failure may be categorized as structural degeneration (calcification, tears, fibrosis, flail), nonstructural degeneration (pannus), thrombosis, and endocarditis. Calcification is the most common form of structural valve degeneration. Predictors of bioprosthetic valve failure include valves implanted in the mitral position, younger age, and type of valve (porcine versus bovine pericardial). Failed bioprosthetic valves are managed with either redo surgical replacement or transcatheter valve-in-valve implantation.

Summary: Several modes of bioprosthetic valve failure exist, which vary based on patient, implant position, and valve characteristics. Further research is required to characterize factors associated with early failure to delay structural valve degeneration and improve patient prognosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HCO.0000000000000711DOI Listing
March 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/ajt.15724DOI Listing
May 2020

Severely calcified bicuspid aortic valve stenosis after valve-sparing root replacement: A word of caution.

J Card Surg 2020 Feb 15;35(2):454-456. Epub 2019 Nov 15.

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

A 58-year-old man was admitted for reoperation for severe aortic stenosis in a previously preserved bicuspid aortic valve (BAV). He had undergone valve-sparing root replacement (VSSR) for dilated aortic root 6 years ago. Transesophageal echocardiography following VSSR showed good valve function with no aortic incompetence. However, the BAV became stenotic causing shortness of breath. At reoperation, the preserved BAV was noted to be fibrotic and calcified and had a fixed rigid small orifice. It was replaced with a biological valve plus root enlargement. Macroscopic finding showed thickening of the cusps and nodular calcification. Microscopic examination revealed severe nodular calcification.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jocs.14348DOI Listing
February 2020

Fit-For-Purpose PD-L1 Biomarker Testing For Patient Selection in Immuno-Oncology: Guidelines For Clinical Laboratories From the Canadian Association of Pathologists-Association Canadienne Des Pathologistes (CAP-ACP).

Appl Immunohistochem Mol Morphol 2019 Nov/Dec;27(10):699-714

Canadian Immunohistochemistry Quality Control.

Since 2014, programmed cell death protein 1 (PD-1)/programmed cell death ligand 1 (PD-L1) checkpoint inhibitors have been approved by various regulatory agencies for the treatment of multiple cancers including melanoma, lung cancer, urothelial carcinoma, renal cell carcinoma, head and neck cancer, classical Hodgkin lymphoma, colorectal cancer, gastroesophageal cancer, hepatocellular cancer, and other solid tumors. Of these approved drug/disease combinations, a subset also has regulatory agency-approved, commercially available companion/complementary diagnostic assays that were clinically validated using data from their corresponding clinical trials. The objective of this document is to provide evidence-based guidance to assist clinical laboratories in establishing fit-for-purpose PD-L1 biomarker assays that can accurately identify patients with specific tumor types who may respond to specific approved immuno-oncology therapies targeting the PD-1/PD-L1 checkpoint. These recommendations are issued as 38 Guideline Statements that address (i) assay development for surgical pathology and cytopathology specimens, (ii) reporting elements, and (iii) quality assurance (including validation/verification, internal quality assurance, and external quality assurance). The intent of this work is to provide recommendations that are relevant to any tumor type, are universally applicable and can be implemented by any clinical immunohistochemistry laboratory performing predictive PD-L1 immunohistochemistry testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/PAI.0000000000000800DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6887625PMC
July 2020

Developing a pan-cancer research autopsy programme.

J Clin Pathol 2019 Oct 1;72(10):689-695. Epub 2019 Jul 1.

Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA

Aims: Rapid procurement of a wide variety of metastatic and primary cancers and normal tissues after death through rapid autopsy opens largely unexplored avenues in cancer research. We describe a high-volume rapid research autopsy programme at a large academic medical centre.

Methods: Advanced-stage cancer patients, most commonly inpatients in palliative care facilities, were approached to participate in a cancer research autopsy programme with the goal of acquiring multidimensionally annotated tissue for cancer research. On death of an enrolled patient, a predetermined notification plan was enacted, with the medical oncologist/clinical research coordinator informing a team of pathologists, researchers and allied staff. Quality assurance metrics were measured. Thereafter, tissues were annotated in a tissue bioinformatics database and linked to electronic patient records. All banked tissues were reviewed for tumour integrity, including DNA and RNA quality.

Results: Over 100 rapid research autopsies from diverse cancer sites were performed, and specimens were procured and annotated with detailed clinical information, including treatment and response. Tissues were successfully enabling studies of tumour immunology, xenografts, genomics and proteomics.

Conclusions: Large-scale rapid procurement and biobanking of cancer tissues from a rapid autopsy programme is feasible. Multidisciplinary integration between health and administrative staff from medical oncology, palliative care, pathology and biospecimen sciences is critical for the success of this challenging endeavour.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jclinpath-2019-205874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817699PMC
October 2019

Novel mediators of aneurysm progression in bicuspid aortic valve disease.

J Mol Cell Cardiol 2019 07 29;132:71-83. Epub 2019 Apr 29.

Division of Cardiovascular Surgery, Toronto General Hospital Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, ON, Canada. Electronic address:

Bicuspid aortic valve (BAV) disease is a congenital abnormality that is associated with ascending aortic aneurysm yet many of the molecular mechanisms remain unknown. To identify novel molecular mechanisms of aneurysm formation we completed microarray analysis of the proximal (severely dilated) and distal (less dilated) regions of the ascending aorta from five patients with BAV. We identified 180 differentially expressed genes, 40 of which were validated by RT-qPCR. Most genes had roles in inflammation and endothelial cell function including cytokines and growth factors, cell surface receptors and the Activator Protein 1 (AP-1) transcription factor family (FOS, FOSB and JUN) which was chosen for further study. AP-1 was differentially expressed within paired BAV aneurysmal samples (n = 8) but not Marfan patients (n = 5). FOS protein was significantly enriched in BAV aortas compared to normal aortas but unexpectedly, ERK1/2 activity, an upstream regulator of FOS was reduced. ERK1/2 activity was restored when BAV smooth muscle cells were cultured in vitro. An mRNA-miRNA network within paired patient samples identified AP-1 as a central hub of miRNA regulation. FOS knockdown in BAV SMCs increased expression of miR-27a, a stretch responsive miRNA. AP-1 and miR-27a were also dysregulated in a mouse model of aortic constriction. In summary, this study identified a central role for AP-1 signaling in BAV aortic dilatation by using paired mRNA-miRNA patient sample. Upstream analysis of AP-1 regulation showed that the ERK1/2 signaling pathway is dysregulated and thus represents a novel chain of mediators of aortic dilatation in BAV which should be considered in future studies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yjmcc.2019.04.022DOI Listing
July 2019

Primary cardiac sarcomas: A multi-national retrospective review.

Cancer Med 2019 01 21;8(1):104-110. Epub 2018 Dec 21.

Sarcoma Department, Mount Sinai Hospital, Toronto, Ontario, Canada.

Background: Primary cardiac sarcoma (PCS) is a rare but often fatal disease. The current study aimed to analyze the impact of baseline demographics, local and systemic therapies in a contemporary cohort.

Methods: Clinical records of PCS across six institutions in three continents were reviewed. Kaplan-Meier method was used to estimate survival. Cox proportional hazard model was used to determine variables impacting progression-free survival (PFS) or overall survival (OS).

Results: Sixty-one patients with PCS (1996-2016) were identified. The median age at diagnosis was 46 (range 18-79); 36% (n = 22) presented with metastatic disease. The most common histology was angiosarcoma (n = 24, 39%). A total of 46 patients received surgery (75%) but only 5 (8%) patients achieved R0 resection. Multi-modality treatment to the primary tumor was given to 28 patients (46%; localized disease 23/39 (59%); metastatic disease 5/22 (23%)). The median OS for the entire cohort was 17.5 months (95% CI 9.5-20.6), with seven (11%) patients surviving longer than 36 months. On multi-variate analysis, age <65 (P = 0.01) was the only significant favorable prognostic factor. For first-line palliative chemotherapy, the median PFS was 4.4 months (95% CI 2.9-7.7 months). The best response for first-line chemotherapy was 32% (CR = 1, PR = 9). No significant improvement in OS was identified in patients presenting throughout the 20-year period of this review.

Conclusion: Younger age at diagnosis was associated with improved outcome although the prognosis of PCS remains poor. Given the lack of improvement in survival, further dedicated research is required.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/cam4.1897DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6346258PMC
January 2019

Giant right atrial aneurysm.

Interact Cardiovasc Thorac Surg 2019 04;28(4):645-646

Department of Cardiovascular Surgery, Toronto General Hospital, Toronto, ON, Canada.

Only a handful of congenital aneurysms of the right atrium have been reported in the literature. They are most commonly found in the third decade of life, and the differential diagnosis depends on the patient's age profile. They are associated with 5% risk of sudden cardiac death. Once diagnosed, they should be surgically removed even in the absence of symptoms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/icvts/ivy304DOI Listing
April 2019

Multimodality Imaging of a Rare Atrioventricular Nodal Tumor.

Circ Cardiovasc Imaging 2018 10;11(10):e008159

Cardiothoracic Division, Department of Medical Imaging, Joint Department of Medical Imaging (E.T.N.), Peter Munk Cardiac Center, Toronto General Hospital, ON, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCIMAGING.118.008159DOI Listing
October 2018

Antimalarial-induced Cardiomyopathy in Systemic Lupus Erythematosus: As Rare as Considered?

J Rheumatol 2019 04 15;46(4):391-396. Epub 2018 Oct 15.

From the University of Toronto Lupus Clinic, Toronto Western Hospital, Centre for Prognosis Studies in the Rheumatic Diseases, University Health Network; University of Toronto, Krembil Research Institute; Department of Cardiology, University of Toronto, Women's College Hospital; Mecklinger Family and Posluns Family Cardiac Catheterization Research Laboratory, Department of Medicine, Division of Cardiology, Mount Sinai Hospital, University of Toronto; Department of Laboratory Medicine and Pathobiology, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada.

Objective: Antimalarials (AM) are recommended for all systemic lupus erythematosus (SLE) patients without specific contraindications. Their main adverse effect is retinal damage; however, heart disease has been described in isolated cases. The aim of our study is to describe 8 patients with AM-induced cardiomyopathy (AMIC) in a defined SLE cohort.

Methods: Patients attending the Toronto Lupus Clinic and diagnosed with definite (based on endomyocardial biopsy; EMB) and possible AMIC were included [based on cardiac magnetic resonance imaging (cMRI) and other investigations].

Results: Eight female patients (median age 62.5 yrs, disease duration 35 yrs, AM use duration 22 yrs) were diagnosed with AMIC in the past 2 years. Diagnosis was based on EMB in 3 (extensive cardiomyocyte vacuolation, intracytoplasmic myelinoid, and curvilinear bodies). In 4 patients, cMRI was highly suggestive of AMIC (ventricular hypertrophy and/or atrial enlargement and late gadolinium enhancement in a nonvascular pattern). Another patient was diagnosed with complete atrioventricular block, left ventricular and septal hypertrophy, along with concomitant ocular toxicity. All patients had abnormal cardiac troponin I (cTnI) and brain natriuretic peptide (BNP), whereas 7/8 also had chronically elevated creatine phosphokinase. During followup, 1 patient died from refractory heart failure. In the remaining patients, hypertrophy regression and a steady decrease of heart biomarkers were observed after AM cessation.

Conclusion: Once considered extremely rare, AMIC seems to be underrecognized, probably because of the false attribution of heart failure or hypertrophy to other causes. Certain biomarkers (cTnI, BNP) and imaging findings may lead to early diagnosis and enhance survival.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3899/jrheum.180124DOI Listing
April 2019

Adipose tumors of the heart.

J Card Surg 2018 Aug 10;33(8):432-437. Epub 2018 Jul 10.

Division of Cardiac Surgery, Peter Munk Cardiac Centre, Toronto General Hospital, University of Toronto, Toronto, Canada.

Background: Primary cardiac adipose tumors are rare. There are two distinct pathologically defined entities that represent this tumor type: lipoma and lipomatous hypertrophy of the interatrial septum (LHIS). We present a single-center experience with these tumors and demonstrate that the location may not correspond to the pathologic diagnosis.

Methods: A retrospective review of a prospectively collected cardiac surgery database from January 1990 to July 2016 identified 254 cases of surgically treated primary cardiac tumors at our Institution. Of these, 06/254 (2%) were primary adipose tumors.

Results: In 3/6 (50%) cases, patients were asymptomatic or had symptoms referable to other known intracardiac lesions. Five patients (83%) had preserved ventricular function. In 4/6 cases (67%), the tumor was identified preoperatively. All patients presented in New York Heart Association functional class ≤2. Pathologic diagnosis of LHIS was made in 5/6 cases (83%), with 2/5 LHIS (40%) located in the interatrial septum. A bovine pericardial patch was utilized for reconstruction following tumor resection in 3/6 cases (50%). Mean cardiopulmonary bypass time was 88 ± 43 min. All the patients tolerated the procedure well without any postoperative complications.

Conclusions: Primary cardiac adipose tumors are responsible for a small portion of all primary heart tumors. Surgical resection provided excellent outcomes, and did not affect cardiac performance, in spite of the need for extensive resections. LHIS was identified in locations other than the interatrial septum and was usually symptomatic.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jocs.13763DOI Listing
August 2018

GLP-1 Receptor Expression Within the Human Heart.

Endocrinology 2018 04;159(4):1570-1584

Department of Medicine, Lunenfeld-Tanenbaum Research Institute, Mt. Sinai Hospital, Toronto, Ontario, Canada.

Glucagonlike peptide-1 receptor (GLP-1R) agonists, which are used to treat type 2 diabetes and obesity, reduce the rates of myocardial infarction and cardiovascular death. GLP-1R has been localized to the human sinoatrial node; however, its expression in ventricular tissue remains uncertain. Here we studied GLP-1R expression in the human heart using GLP-1R-directed antisera, quantitative polymerase chain reaction (PCR), reverse transcription PCR to detect full-length messenger RNA (mRNA) transcripts, and in situ hybridization (ISH). GLP1R mRNA transcripts, encompassing the entire open reading frame, were detected in all four cardiac chambers from 15 hearts at levels approximating those detected in human pancreas. In contrast, cardiac GLP2R expression was relatively lower, and cardiac GCGR expression was sporadic and not detected in the left ventricle. GLP1R mRNA transcripts were not detected in RNA from human cardiac fibroblasts, coronary artery endothelial, or vascular smooth muscle cells. Human Brunner glands and pancreatic islets exhibited GLP-1R immunopositivity and abundant expression of GLP1R mRNA transcripts by ISH. GLP1R transcripts were also detected by ISH in human cardiac sinoatrial node tissue. However, definitive cellular localization of GLP1R mRNA transcripts or immunoreactive GLP-1R protein within human cardiomyocytes or cardiac blood vessels remained elusive. Moreover, validated GLP-1R antisera lacked sufficient sensitivity to detect expression of the endogenous islet or cardiac GLP-1R by Western blotting. Hence, although human cardiac ventricles express the GLP1R, the identity of one or more ventricular cell type(s) that express a translated GLP1R protein requires further clarification with highly sensitive methods of detection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/en.2018-00004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5939638PMC
April 2018

Reimplantation for Marfan syndrome: If it ain't broke….

J Thorac Cardiovasc Surg 2018 01 5;155(1):52-53. Epub 2017 Sep 5.

Peter Munk Cardiac Centre, Division of Cardiac Surgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jtcvs.2017.08.085DOI Listing
January 2018

Outflow Graft Occlusion of the HeartMate 3 Left Ventricular Assist Device.

Circ Heart Fail 2017 09;10(9)

From the Department of Medicine (J.G.D.P., Y.M., M.A., H.J.R., F.B.), Division of Cardiology (J.G.D.P., Y.M., M.A., H.J.R., F.B.), Division of Cardiovascular Surgery, Department of Surgery (M.R., J.A., V.R.), Department of Medical Imaging, Peter Munk Cardiac Centre (B.J.W.), Ted Rogers Centre for Heart Research (M.R., H.J.R., F.B., V.R.), and Laboratory Medicine and Pathology (J.B.), Toronto General Hospital, University of Toronto, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.117.004275DOI Listing
September 2017

p53 and Mdm2 act synergistically to maintain cardiac homeostasis and mediate cardiomyocyte cell cycle arrest through a network of microRNAs.

Cell Cycle 2017 26;16(17):1585-1600. Epub 2017 Jul 26.

a Institute of Medical Science , University of Toronto , Toronto , Ontario , Canada.

Defining the roadblocks responsible for cell cycle arrest in adult cardiomyocytes lies at the core of developing cardiac regenerative therapies. p53 and Mdm2 are crucial mediators of cell cycle arrest in proliferative cell types, however, little is known about their function in regulating homeostasis and proliferation in terminally differentiated cell types, like cardiomyocytes. To explore this, we generated a cardiac-specific conditional deletion of p53 and Mdm2 (DKO) in adult mice. Herein we describe the development of a dilated cardiomyopathy, in the absence of cardiac hypertrophy. In addition, DKO hearts exhibited a significant increase in cardiomyocyte proliferation. Further evaluation showed that proliferation was mediated by a significant increase in Cdk2 and cyclin E with downregulation of p21 and p27. Comparison of miRNA expression profiles from DKO mouse hearts and controls revealed 11 miRNAs that were downregulated in the DKO hearts and enriched for mRNA targets involved in cell cycle regulation. Knockdown of these miRNAs in neonatal rat cardiomyocytes significantly increased cytokinesis with an upregulation in the expression of crucial cell cycle regulators. These results illustrate the importance of the cooperative activities of p53 and Mdm2 in a network of miRNAs that function to impose a barrier against aberrant cardiomyocyte cell cycle re-entry to maintain cardiac homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15384101.2017.1346758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5587026PMC
May 2018

Pancreatic Neuroendocrine Tumor Producing Insulin and Vasopressin.

Endocr Pathol 2018 Mar;29(1):15-20

Department of Medicine, Princess Margaret Cancer Centre, University Health Network, 610 University Avenue, Room 7-327, Toronto, ON, M5G 2M9, Canada.

The objective of the study is to report a rare case of pancreatic neuroendocrine tumor (pNET) producing insulin and vasopressin. We describe the clinical presentation and management of a metastatic pNET with refractory hypoglycemia and progressive severe hyponatremia. A 52-year-old patient had abdominal pain leading to the diagnosis of a tumor that was initially presumed to be splenic in origin. Investigations ultimately identified a pancreatic mass that on biopsy proved to be a pNET. Eventually, he developed extensive liver metastases, and with tumor progression, he manifested hypoglycemia and severe hyponatremia. He was managed with multiple therapies including somatostatin analogue, peptide-receptor-radionuclide-therapy (PRRT), diazoxide, and everolimus; none of these therapeutic modalities was successful in controlling functional and structural progression of the tumor. Ultimately, the pNET proved fatal and autopsy confirmed widely metastatic disease that stained strongly and diffusely for vasopressin, a feature not seen in the previous liver biopsy. This case illustrates the challenges of diagnosis and management of aggressive insulin-producing pNETs and highlights the potential concomitant ectopic production of vasopressin leading to refractory hyponatremia.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12022-017-9492-5DOI Listing
March 2018

Sequential spontaneous severe aortic and mitral regurgitation.

Hellenic J Cardiol 2016 Nov - Dec;57(6):438-440. Epub 2016 Nov 16.

Department of Cardiovascular Surgery, St Michael's Hospital, Toronto, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.hjc.2016.11.010DOI Listing
January 2018

A Matched Cohort Study of Patients With End-Stage Heart Failure from Anthracycline-Induced Cardiomyopathy Requiring Advanced Cardiac Support.

Am J Cardiol 2016 Nov 23;118(10):1539-1544. Epub 2016 Aug 23.

Ted Rogers Program in Cardiotoxicity Prevention, Peter Munk Cardiac Center, University Health Network, University of Toronto, Toronto, Ontario, Canada; Ted Rogers Center of Excellence in Heart Function, Peter Munk Cardiac Center, University Health Network, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Anthracycline-induced cardiomyopathy (AIC) may progress to end-stage heart failure requiring mechanical circulatory support or orthotopic heart transplantation (OHT). Previous studies have described important clinical differences between AIC and nonischemic cardiomyopathy (NIC) cohorts requiring these advanced interventions. Therefore, we sought to extend this literature by comparing echocardiographic parameters, treatment strategies, and the prognosis between matched patients from these cohorts. This is a retrospective matched cohort study. All patients who received a ventricular assist device or OHT at a large Canadian center were reviewed (n = 421; 1988 to 2015) and subjects with clinical and pathologic evidence of AIC were included (n = 17, 4.0%). A comparison cohort with idiopathic NIC from the same database, matched 3:1 for age, gender, ethnicity, and year of heart failure onset was selected. The Mann-Whitney rank-sum and Fisher's exact tests were used for comparisons. Patients with AIC were predominantly women (70.6%) with heart failure diagnosed at age 40.2 ± 15.8 and 8.3 ± 8.9 years after anthracycline treatment. Compared with NIC, no differences were seen in co-morbidities, echocardiographic measures, the proportion of patients receiving a defibrillator, ventricular assist device, or OHT, the incidence of graft failure, and all-cause mortality. In contrast to other studies, AIC was not associated with a higher incidence of right ventricular dysfunction. A greater proportion of patients with AIC developed cancer (recurrence or new primary) post-OHT (21.4% vs 2.3%, p = 0.042). In conclusion, we demonstrate that when matched cohorts of patients with end-stage heart failure secondary to AIC and idiopathic NIC are compared, they are similar with respect to co-morbidities, degree of ventricular dysfunction, and advanced therapeutics used. The prognosis with OHT is also similar.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.amjcard.2016.08.020DOI Listing
November 2016

Hydroxychloroquine-Induced Cardiomyopathy in Systemic Lupus Erythematosus.

J Clin Rheumatol 2016 Aug;22(5):287-8

University of Toronto Lupus Clinic Centre for Prognosis Studies in the Rheumatic Diseases Toronto Western Hospital Toronto, Ontario, Canada Department of Medicine University of Toronto and Department of Medicine Women's College Hospital Toronto, Ontario, Canada Mecklinger Family and Posluns Family Cardiac Catheterization Research Laboratory Department of Medicine Division of Cardiology Mount Sinai Hospital University of Toronto Toronto, Ontario, Canada Fred A. Litwin Family Centre in Genetic Medicine Department of Medicine Mount Sinai Hospital University of Toronto Toronto, Ontario, Canada University Health Network Pathology Department Toronto General Research Institute Toronto, Ontario, Canada University of Toronto Lupus Clinic Centre for Prognosis Studies in the Rheumatic Diseases Toronto Western Hospital Toronto, Ontario, Canada

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/RHU.0000000000000400DOI Listing
August 2016

Progressive Aortic Dilation Is Regulated by miR-17-Associated miRNAs.

J Am Coll Cardiol 2016 06;67(25):2965-77

Division of Cardiovascular Surgery, Toronto General Research Institute and Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Department of Surgery, Division of Cardiac Surgery, University of Toronto, Toronto, Ontario, Canada. Electronic address:

Background: Patients with a bicuspid aortic valve (BAV) are at increased risk for progressive aortic dilation associated with extracellular matrix (ECM) degradation by matrix metalloproteinases (MMP). However, the mechanisms responsible for initiating this process are unknown. In the heart, MMP activity is regulated by micro-ribonucleic acid-17 (miR-17)-related downregulation of tissue inhibitors of metalloproteinases (TIMP); a similar process may exist in the aorta.

Objectives: This study sought to ascertain whether aortic matrix degradation in BAV patients progresses by miR-17-related miRNA regulation of TIMP-MMP.

Methods: To eliminate confounding patient-related factors, severely dilated and less dilated aortic tissue samples were collected from 12 BAV patients. Gene and protein expression levels were evaluated in paired tissue samples from the same patient and were compared to aortic samples from 16 patients with aortas that appeared to be normal.

Results: Gene expression analyses confirmed increased expression of miR-17-related miRNAs in less dilated compared with severely dilated tissue from the same patient or normal aortic sample. TIMP-1, -2, and -3 were significantly decreased, and MMP2 activity was significantly increased in less dilated samples, suggesting that this normal-looking tissue was in the early stages of ECM degradation. Smooth muscle cells isolated from normal or BAV aortas transfected with an miR-17 mimic had decreased TIMP-1 and -2 expression and increased MMP2 activity, whereas the opposite effects were seen with an miR-17 inhibitor, suggesting that miR-17 may control the TIMP-MMP balance in these tissues. Luciferase reporter assays demonstrated that miR-17 regulated TIMP-1 and -2 expression.

Conclusions: Our in vitro and in vivo studies taken together confirm that miR-17 directly regulates TIMP-1 and -2. Less dilated aortic BAV tissue may be in the initial stages of dilation under the control of miR-17-related miRNAs. New therapies that inhibit these miRNAs may prevent aortic dilation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jacc.2016.04.027DOI Listing
June 2016

Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association For European Cardiovascular Pathology: II. Noninflammatory degenerative diseases - nomenclature and diagnostic criteria.

Cardiovasc Pathol 2016 May-Jun;25(3):247-257. Epub 2016 Mar 12.

University of Ottawa, Ottawa, Ontario, Canada.

Surgical aortic specimens are usually examined in Pathology Departments as a result of treatment of aneurysms or dissections. A number of diseases, genetic syndromes (Marfan syndrome, Loeys-Dietz syndrome, etc.), and vasculopathic aging processes involved in vascular injury can cause both distinct and nonspecific histopathologic changes with degeneration of the media as a common denominator. Terminology for these changes has varied over time leading to confusion and inconsistencies. This consensus document has established a revised, unified nomenclature for the variety of noninflammatory degenerative aortic histopathologies seen in such specimens. Older terms such as cystic medial necrosis and medionecrosis are replaced by more technically accurate terms such as mucoid extracellular matrix accumulation (MEMA), elastic fiber fragmentation and/or loss, and smooth muscle cell nuclei loss. A straightforward system of grading is presented to gauge the extent of medial degeneration and synoptic reporting tables are provided. Herein we present a standardized nomenclature that is accessible to general pathologists and useful for future publications describing these entities.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carpath.2016.03.002DOI Listing
January 2017

Update on rheumatic heart disease.

Curr Opin Cardiol 2016 Mar;31(2):162-8

aDivision of Cardiac Surgery, St Michael's Hospital bDivision of Pathology, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.

Purpose Of Review: The purpose is to provide a broad overview of the current state of knowledge of pathogenesis, diagnosis, and management of rheumatic heart disease (RHD).

Recent Findings: Studies on pathogenesis of RHD have focused on autoimmunity because of molecular mimicry between the streptococcal M antigen α-helical coiled-coil structure and sarcomeric proteins such as myosin and tropomyosin. More recently, nonsarcomeric autoantigens, endothelial injury and the innate immune system have been proposed to play key roles in the pathogenesis of RHD. In the 2015 revised Jones Criteria, the importance of echocardiography and subclinical carditis in the diagnosis of acute rheumatic fever is highlighted. Experimental studies with targeted anti-inflammatory therapeutics have been largely unsuccessful and the only established treatment is still lifelong antibiotics. Efforts to improve patient selection and outcomes with percutaneous mitral balloon valvuloplasty are ongoing. With regard to surgical management, several groups have demonstrated excellent operative and midterm outcomes from valve repair as opposed to valve replacement.

Summary: There are still many unanswered questions regarding RHD pathogenesis. The only accepted medical treatment is still long-term antibiotic therapy, whereas advances in mitral repair techniques have led to successful durable repairs being performed in high-volume, expert centers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/HCO.0000000000000269DOI Listing
March 2016

Quantification of Myocardial Extracellular Volume Fraction with Cardiac MR Imaging in Thalassemia Major.

Radiology 2016 Jun 10;279(3):720-30. Epub 2015 Dec 10.

Department of Medical Imaging (K.H., E.T.N., P.T., I.Y.Y., M.S.S., B.J.W.) and Division of Cardiology (P.T.), Peter Munk Cardiac Centre, University Health Network, University of Toronto, 585 University Ave, NCSB-1C557, Toronto, ON, Canada M5G 2N2; Division of Hematology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada (R.W.); Siemens AG Healthcare, Erlangen, Germany (A.G.); Department of Corporate Research, Siemens Corporation, Princeton, NJ (M.P.J.); and Division of Pathology, Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, Ontario, Canada (J.B.).

Purpose To quantify myocardial extracellular volume (ECV) by using cardiac magnetic resonance (MR) imaging in thalassemia major and to investigate the relationship between ECV and myocardial iron overload. Materials and Methods With institutional review board approval and informed consent, 30 patients with thalassemia major (mean age ± standard deviation, 34.6 years ± 9.5) and 10 healthy control subjects (mean age, 31.5 years ± 4.4) were prospectively recruited (clinicaltrials.gov identification number NCT02090699). Nineteen patients (63.3%) had prior myocardial iron overload (defined as midseptal T2* < 20 msec on any prior cardiac MR images). Cardiac MR imaging at 1.5 T included cine steady-state free precession for ventricular function, T2* for myocardial iron quantification, and unenhanced and contrast material-enhanced T1 mapping. ECV was calculated with input of the patient's hematocrit level. Peak systolic global longitudinal strain by means of speckle tracking was assessed with same-day transthoracic echocardiography. Statistical analysis included use of the two-sample t test, Fisher exact test, and Spearman correlation. Results Unenhanced T1 values were significantly lower in patients with prior myocardial iron overload than in control subjects (850.3 ± 115.1 vs 1006.3 ± 35.4, P < .001) and correlated strongly with T2* values (r = 0.874, P < .001). Patients with prior myocardial iron overload had higher ECV than did patients without iron overload (31.3% ± 2.8 vs 28.2% ± 3.4, P = .030) and healthy control subjects (27.0% ± 3.1, P = .003). There was no difference in ECV between patients without iron overload and control subjects (P = .647). ECV correlated with lowest historical T2* (r = -0.469, P = .010) but did not correlate significantly with left ventricular ejection fraction (r = -0.216, P = .252) or global longitudinal strain (r = -0.164, P = .423). Conclusion ECV is significantly increased in thalassemia major and is associated with myocardial iron overload. These abnormalities may potentially reflect diffuse interstitial myocardial fibrosis. (©) RSNA, 2015 Online supplemental material is available for this article.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.2015150341DOI Listing
June 2016

Distal coronary embolization following acute myocardial infarction increases early infarct size and late left ventricular wall thinning in a porcine model.

J Cardiovasc Magn Reson 2015 Dec 1;17:106. Epub 2015 Dec 1.

Schulich Heart Centre, Sunnybrook Health Sciences Center, 2075 Bayview Avenue, Room D-406, Toronto, ON, M4N 3M5, Canada.

Background: Distal coronary embolization (DCE) of thrombotic material occurs frequently during percutaneous interventions for acute myocardial infarction and can alter coronary flow grades. The significance of DCE on infarct size and myocardial function remains unsettled. The aims of this study were to evaluate the effects of DCE sufficient to cause no-reflow on infarct size, cardiac function and ventricular remodeling in a porcine acute myocardial infarction model.

Methods And Results: Female Yorkshire pigs underwent 60 min balloon occlusion of the left anterior descending coronary artery followed by reperfusion and injection of either microthrombi (prepared from autologous porcine blood) sufficient to cause no-reflow (DCE), or saline (control). Animals were sacrificed at 3 h (n = 5), 3 days (n = 20) or 6 weeks (n = 20) post-AMI. Cardiovascular magnetic resonance (CMR), serum troponin-I, and cardiac gelatinase (MMP) and survival kinase (Akt) activities were assessed. At 3d, DCE increased infarct size (CMR: 18.8% vs. 14.5%, p = 0.04; serum troponin-I: 13.3 vs. 6.9 ng/uL, p < 0.05) and MMP-2 activity levels (0.81 vs. 0.49, p = 0.002), with reduced activation of Akt (0.06 versus 0.26, p = 0.02). At 6 weeks, there were no differences in infarct size, ventricular volume or ejection fraction between the two groups, although infarct transmurality (70% vs. 57%, p< 0.04) and ventricular thinning (percent change in mid anteroseptal wall thickness:-25.6% vs. 0.7%, p = 0.03) were significantly increased in the DCE group.

Conclusions: DCE increased early infarct size, but without affecting later infarct size, cardiac function or ventricular volumes. The significance of the later remodelling changes (ventricular thinning and transmurality) following DCE, possibly due to changes in MMP-2 activity and Akt activation, merits further study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12968-015-0197-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666124PMC
December 2015

Consensus statement on surgical pathology of the aorta from the Society for Cardiovascular Pathology and the Association for European Cardiovascular Pathology: I. Inflammatory diseases.

Cardiovasc Pathol 2015 Sep-Oct;24(5):267-78. Epub 2015 May 16.

University of Ottawa, Ottawa, Ontario, Canada.

Inflammatory diseases of the aorta include routine atherosclerosis, aortitis, periaortitis, and atherosclerosis with excessive inflammatory responses, such as inflammatory atherosclerotic aneurysms. The nomenclature and histologic features of these disorders are reviewed and discussed. In addition, diagnostic criteria are provided to distinguish between these disorders in surgical pathology specimens. An initial classification scheme is provided for aortitis and periaortitis based on the pattern of the inflammatory infiltrate: granulomatous/giant cell pattern, lymphoplasmacytic pattern, mixed inflammatory pattern, and the suppurative pattern. These inflammatory patterns are discussed in relation to specific systemic diseases including giant cell arteritis, Takayasu arteritis, granulomatosis with polyangiitis (Wegener's), rheumatoid arthritis, sarcoidosis, ankylosing spondylitis, Cogan syndrome, Behçet's disease, relapsing polychondritis, syphilitic aortitis, and bacterial and fungal infections.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.carpath.2015.05.001DOI Listing
June 2016
-->