Michael Sean McMurtry

2014 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation

Atrial fibrillation (AF) is an extremely common clinical problem with an important population morbidity and mortality burden. The management of AF is complex and fraught with many uncertain and contentious issues, which are being addressed by extensive ongoing basic and clinical research. The Canadian Cardiovascular Society AF Guidelines Committee produced an extensive set of evidence-based AF management guidelines in 2010 and updated them in the areas of anticoagulation and rate/rhythm control in 2012. In late 2013, the committee judged that sufficient new information regarding AF management had become available since 2012 to warrant an update to the Canadian Cardiovascular Society AF Guidelines. After extensive evaluation of the new evidence, the committee has updated the guidelines for: (1) stroke prevention principles; (2) anticoagulation of AF patients with chronic kidney disease; (3) detection of AF in patients with stroke; (4) investigation and management of subclinical AF; (5) left atrial appendage closure in stroke prevention; (6) emergency department management of AF; (7) periprocedural anticoagulation management; and (8) rate and rhythm control including catheter ablation. This report presents the details of the updated recommendations, along with their background and rationale. In addition, a complete set of presently applicable recommendations, those that have been updated and those that remain in force from previous guideline versions, is provided in the Supplementary Material.

Pyruvate dehydrogenase inhibition by the inflammatory cytokine TNFα contributes to the pathogenesis of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a vascular remodeling disease characterized by enhanced proliferation and suppressed apoptosis of pulmonary artery smooth muscle cells (PASMC). This apoptosis resistance is characterized by PASMC mitochondrial hyperpolarization [in part, due to decreased pyruvate dehydrogenase (PDH) activity], decreased mitochondrial reactive oxygen species (mROS), downregulation of Kv1.5, increased [Ca++]i, and activation of the transcription factor nuclear factor of activated T cells (NFAT). Inflammatory cells are present within and around the remodeled arteries and patients with PAH have elevated levels of inflammatory cytokines, including tumor necrosis factor-α (TNFα). We hypothesized that the inflammatory cytokine TNFα inhibits PASMC PDH activity, inducing a PAH phenotype in normal PASMC. We exposed normal human PASMC to recombinant human TNFα and measured PDH activity. In TNFα-treated cells, PDH activity was significantly decreased. Similar to exogenous TNFα, endogenous TNFα secreted from activated human CD8+ T cells, but not quiescent T cells, caused mitochondrial hyperpolarization, decreased mROS, decreased K+ current, increased [Ca++]i, and activated NFAT in normal human PASMC. A TNFα antibody completely prevented, while recombinant TNFα mimicked the T cell-induced effects. In vivo, the TNFα antagonist etanercept prevented and reversed monocrotaline (MCT)-induced PAH. In a separate model, T cell deficient rats developed less severe MCT-induced PAH compared to their controls. We show that TNFα can inhibit PASMC PDH activity and induce a PAH phenotype. Our work supports the use of anti-inflammatory therapies for PAH.

Canadian Stroke Best Practice Recommendations: secondary prevention of stroke guidelines, update 2014

Every year, approximately 62 000 people with stroke and transient ischemic attack are treated in Canadian hospitals. The 2014 update of the Canadian Secondary Prevention of Stroke guideline is a comprehensive summary of current evidence-based recommendations for clinicians in a range of settings, who provide care to patients following stroke. Notable changes in this 5th edition include an emphasis on treating the highest risk patients who present within 48 h of symptom onset with transient or persistent motor or speech symptoms, who need to be transported to the closest emergency department with capacity for advanced stroke care; a recommendation for brain and vascular imaging (of the intra- and extracranial vessels) to be completed urgently using computed tomography/computed tomography angiography; prolonged cardiac monitoring for patients with suspective cardioembolic stroke but without evidence for atrial fibrillation on electrocardiogram or holter monitoring; and de-emphasizing the need for routine echocardiogram. The Canadian Stroke Best Practice Recommendations include a range of supporting materials such as implementation resources to facilitate the adoption of evidence to practice, and related performance measures to enable monitoring of uptake and effectiveness of the recommendations using a standardized approach. The guidelines further emphasize the need for a systems approach to stroke care, involving an interprofessional team, with access to specialists regardless of patient location, and the need to overcome geographical barriers to ensure equity in access within a universal health-care system.

Angiotensin-Converting Enzyme 2 Is a Critical Determinant of Angiotensin II–Induced Loss of Vascular Smooth Muscle Cells and Adverse Vascular Remodeling

Angiotensin-converting enzyme (ACE) 2 is a key negative regulator of the renin–angiotensin system and metabolizes angiotensin II (Ang II) into Ang 1 to 7. Ang II is a vasoactive peptide, which plays an important role in vascular disease. The objective of the present study was to define the role of ACE2 in pathological vascular remodeling. We found upregulation of ACE2 in dilated human aorta with bicuspid aortic valve and in murine aorta in response to Ang II. Ex vivo pressure myography showed increased vascular stiffness in ACE2 knockout (KO) mesenteric arteries in response to Ang II (1.5 mg/kg per day) and with aging. Histological analyses revealed reduced media-to-lumen ratio in ACE2KO mesenteric arteries with loss of vascular smooth muscle cells. Aortic vascular smooth muscle cells from ACE2KO mice showed markedly increased reactive oxygen species and apoptosis in response to Ang II along with increased cleaved caspase-3 and cleaved caspase-8 levels in the ACE2KO aorta. Ang II type 1 receptor blockade and Ang 1 to 7 supplementation prevented the increase in Ang II–induced reactive oxygen species and apoptotic cell death. In the aorta, Ang II resulted in thoracic and abdominal aortic dilation with loss of vascular smooth muscle cell density in ACE2KO aorta as revealed by &agr;-smooth muscle actin, calponin staining, and electron microscopy with increased promatrix metalloproteinase 2, matrix metalloproteinase 2, and matrix metalloproteinase 9 levels. ACE2 is upregulated in vascular diseases, and ACE2 deficiency exacerbates Ang II–mediated vascular remodeling driven by increased reactive oxygen species and vascular smooth muscle cell apoptosis. In conclusion, the key counter-regulatory role of ACE2 against an activated renin–angiotensin system provides novel insights into the role of ACE2 in vascular diseases.

The 2014 Atrial Fibrillation Guidelines Companion: A Practical Approach to the Use of the Canadian Cardiovascular Society Guidelines

The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Program has generated a comprehensive series of documents regarding the management of atrial fibrillation (AF) between 2010 and 2014. The guidelines provide evidence-based consensus management recommendations in a broad range of areas. These guidelines have proven useful in informing clinical practice, but often lack detail in specifications related to practical application, particularly for areas in which the evidence base is limited or conflicting. Based on feedback from the community, the CCS Atrial Fibrillation Guidelines Committee has identified a number of areas that require clarification to address commonly asked practical questions related to guidelines application. In the present article a number of such questions are presented and suggestions about how they can be answered are suggested. Among the issues considered are: (1) What duration of AF is clinically significant? (2) How are the risk factors in the CCS Algorithm for selecting anticoagulation therapy derived and defined? (3) How is valvular heart disease defined and how do different forms of valve disease affect the choice of anticoagulant therapy for AF patients? (4) How should we quantify renal dysfunction and how does it affect therapeutic choices? The response to these questions and the underlying logic are provided, along with an indication of future research needed where no specific approach can presently be recommended based on the literature.

2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy

Antiplatelet therapy (APT) has become an important tool in the treatment and prevention of atherosclerotic events, particularly those associated with coronary artery disease. A large evidence base has evolved regarding the relationship between APT prescription in various clinical contexts and risk/benefit relationships. The Guidelines Committee of the Canadian Cardiovascular Society and Canadian Association of Interventional Cardiology publishes regular updates of its recommendations, taking into consideration the most recent clinical evidence. The present update to the 2011 and 2013 Canadian Cardiovascular Society APT guidelines incorporates new evidence on how to optimize APT use, particularly in situations in which few to no data were previously available. The recommendations update focuses on the following primary topics: (1) the duration of dual APT (DAPT) in patients who undergo percutaneous coronary intervention (PCI) for acute coronary syndrome and non-acute coronary syndrome indications; (2) management of DAPT in patients who undergo noncardiac surgery; (3) management of DAPT in patients who undergo elective and semiurgent coronary artery bypass graft surgery; (4) when and how to switch between different oral antiplatelet therapies; and (5) management of antiplatelet and anticoagulant therapy in patients who undergo PCI. For PCI patients, we specifically analyze the particular considerations in patients with atrial fibrillation, mechanical or bioprosthetic valves (including transcatheter aortic valve replacement), venous thromboembolic disease, and established left ventricular thrombus or possible left ventricular thrombus with reduced ejection fraction after ST-segment elevation myocardial infarction. In addition to specific recommendations, we provide values and preferences and practical tips to aid the practicing clinician in the day to day use of these important agents.

Impact of Rural Residence on Warfarin Use and Clinical Events in Patients with Non-Valvular Atrial Fibrillation: A Canadian Population Based Study

Background and Purpose We studied whether anticoagulant use and outcomes differed between rural versus urban Canadian non-valvular atrial fibrillation (NVAF) patients prior to the introduction of direct oral anticoagulant drugs. Methods Retrospective cohort study of 25,284 adult Albertans with NVAF between April 1, 1999 and December 31, 2008. Results Compared to urban patients, rural patients were older (p = 0.0009) and had more comorbidities but lower bleeding risk at baseline. In the first year after NVAF diagnosis, urban patients were less likely to be hospitalized (aOR 0.82, 95%CI 0.77–0.89) or have an emergency department visit for any reason (aOR 0.61, 95%CI 0.56–0.66) but warfarin dispensation rates (72.2% vs 71.8% at 365 days, p = 0.98) and clinical outcomes were similar: 7.8% died in both groups, 3.2% rural vs. 2.8% urban had a stroke or systemic embolism (SSE) (aOR 0.92, 95%CI 0.77–1.11), and 6.6% vs. 5.7% (aOR 0.93, 95%CI 0.81–1.06) had a bleed. Baseline SSE risk did not impact warfarin dispensation (73.0% in those with high vs. 72.8% in those with low CHADS2 score, p = 0.85) but patients at higher baseline bleeding risk were less likely to be using warfarin (69.2% high vs. 73.6% low HASBLED score, p<0.0001) in the first 365 days after diagnosis. In warfarin users, bleeding was more frequent (7.5% vs 6.2%, aHR 1.51 [95%CI 1.33–1.72]) but death or SSE was less frequent (7.0% vs 18.1%, aHR 0.60 [0.54–0.66]). Conclusion Warfarin use and clinical event rates did not differ between rural and urban NVAF patients in a universal access publically-funded healthcare system.

Trends in admission rates and in-hospital stay for venous thromboembolism☆

BACKGROUND Acute venous thromboembolism leads to significant morbidity and mortality. Advances in pharmacotherapy facilitate outpatient care in low-risk acute venous thromboembolism. The proportion of hospitalized acute venous thromboembolism cases and the average length of stay are not known. We sought to identify predictors of hospitalization, changes in hospitalization rates and length of stay of acute venous thromboembolism over a decade in Alberta, Canada. METHODS Using linked administrative health databases, we identified adult patients diagnosed primarily with acute venous thromboembolism between April 2002 and March 2012. We measured trends using Poisson regression, adjusted length of stay using analysis of covariance. We identified predictors of hospitalization using multivariate logistic regression. RESULTS 8198 out of 31,656 acute venous thromboembolism cases were hospitalized. The overall venous thromboembolism admission rates ranged between 23.7% and 27.8% with no evident temporal trend (P=0.10). The average admission rate was 51.9% for pulmonary embolism and 16.1% for deep vein thrombosis. The mean length of stay for deep vein thrombosis and pulmonary embolism remained unchanged with an adjusted mean for venous thromboembolism of 6.9±1.0days. Higher Charlson index, older age, male gender, pulmonary embolism at presentation and multiple comorbidities were associated with hospitalization. Hospitalization was associated with 30-day mortality (odds ratio:2.8, 95% CI: 2.2-3.5) whereas the length of stay was not (odds ratio:1.0, 95% CI: 0.99-1.0). CONCLUSION Hospitalization rates and mean length of stay for acute venous thromboembolism did not change significantly between 2002 and 2012. Advances in pharmacotherapy have not yet reduced hospitalization rates or length of stay for venous thromboembolism.

A type A aortic dissection missed by non-cardiac gated contrast-enhanced computed tomography due to an aortic root dissection flap masquerading as an aortic valve apparatus: a case report

IntroductionThough computed tomographic angiography has very high sensitivity and specificity to diagnose acute aortic dissection, false-negative studies can occur and secondary tests may be required to make the diagnosis.Case presentationWe report the case of a 57-year-old Caucasian man with a typical presentation for acute type A aortic dissection in whom the initial non-cardiac gated computed tomographic angiogram was negative, leading to a delay in surgical management. Transesophageal echocardiography and post hoc 3D reconstruction of the original computed tomographic scan revealed a dissection flap confined to the aortic root, immediately superior to the sinuses of Valsalva and masquerading as part of the aortic valve apparatus.ConclusionThis case demonstrates that false-negative computed tomographic angiograms taken to rule out type A aortic dissection can occur and that secondary imaging tests, such as echocardiography, should be performed in cases in which the pre-test probability of aortic dissection is high. Cardiac gating of computed tomographic angiograms to exclude aortic dissection may enhance diagnostic accuracy.

Sex disparities in hospitalization and mortality rates for venous thromboembolism

Venous thromboembolism (VTE) is a major health problem for both men and women. Whether sex disparities exist for outcomes after acute VTE is unknown. We sought to measure sex-specific rates of hospitalization for and mortality from acute VTE. We used a population-based administrative dataset from Alberta, Canada, covering the years 2002 to 2012. We used Poisson regression to measure the incidence rate ratio for hospitalization and Cox regression to test for sex disparities in short-term all-cause mortality after adjusting for potential confounders. Of those diagnosed with VTE, 55.9% were women. The proportion of hospitalized women for VTE was 24.4 versus 27.8% in men (p < 0.001). The risk adjusted incidence rate ratio for VTE hospitalization increased with age for both sex. While women younger than 80 years old were less likely to be hospitalized than men, sex disparities for the risk of hospitalization were not significant after age 80 (p = 0.93). The adjusted 90-day all-cause mortality rate for women was 4.0% compared to 4.9% in men (adjusted HR = 1.0, p = 0.49). Women with acute VTE were less likely than men to be hospitalized in most age groups, but sex disparities in short-term all-cause mortality were not found.