Administrative data are not sensitive for the detection of peripheral artery disease in the community.

We sought to evaluate whether case ascertainment using administrative health data would be a feasible way to identify peripheral artery disease (PAD) patients from the community. Subjects' ankle-brachial index (ABI) scores from two previous prospective observational studies were linked with International Classification of Diseases (ICD) and Canadian Classification of Interventions (CCI) codes from three administrative databases from April 2002 to March 2012, including the Alberta Inpatient Hospital Database (ICD-10-CA/CCI), Ambulatory Care Database (ICD-10-CA/CCI), and the Practitioner Payments Database (ICD-9-CM). We calculated diagnostic statistics for putative case definitions of PAD consisting of individual code or sets of codes, using an ABI score ⩽ 0.90 as the gold standard. Multivariate logistic regression was performed to investigate additional predictive factors for PAD. Different combinations of diagnostic codes and predictive factors were explored to find out the best algorithms for identifying a PAD study cohort. A total of 1459 patients were included in our analysis. The average age was 63.5 years, 66% were male, and the prevalence of PAD was 8.1%. The highest sensitivity of 34.7% was obtained using the algorithm of at least one ICD diagnostic or procedure code, with specificity 91.9%, positive predictive value (PPV) 27.5% and negative predictive value (NPV) 94.1%. The algorithm achieving the highest PPV of 65% was age ⩾ 70 years and at least one code within 443.9 (ICD-9-CM), I73.9, I79.2 (ICD-10-CA/CCI), or all procedure codes, validated with ABI < 1.0 (sensitivity 5.56%, specificity 99.4% and NPV 84.6%). In conclusion, ascertaining PAD using administrative data scores was insensitive compared with the ABI, limiting the use of administrative data in the community setting.

The validity of ICD codes coupled with imaging procedure codes for identifying acute venous thromboembolism using administrative data.

The purpose of this study was to evaluate the accuracy of using a combination of International Classification of Diseases (ICD) diagnostic codes and imaging procedure codes for identifying deep vein thrombosis (DVT) and pulmonary embolism (PE) within administrative databases. Information from the Alberta Health (AH) inpatients and ambulatory care administrative databases in Alberta, Canada was obtained for subjects with a documented imaging study result performed at a large teaching hospital in Alberta to exclude venous thromboembolism (VTE) between 2000 and 2010. In 1361 randomly-selected patients, the proportion of patients correctly classified by AH administrative data, using both ICD diagnostic codes and procedure codes, was determined for DVT and PE using diagnoses documented in patient charts as the gold standard. Of the 1361 patients, 712 had suspected PE and 649 had suspected DVT. The sensitivities for identifying patients with PE or DVT using administrative data were 74.83% (95% confidence interval [CI]: 67.01-81.62) and 75.24% (95% CI: 65.86-83.14), respectively. The specificities for PE or DVT were 91.86% (95% CI: 89.29-93.98) and 95.77% (95% CI: 93.72-97.30), respectively. In conclusion, when coupled with relevant imaging codes, VTE diagnostic codes obtained from administrative data provide a relatively sensitive and very specific method to ascertain acute VTE.

The 2023 Canadian Cardiovascular Society Clinical Practice Update on Management of the Patient With a Prolonged QT Interval.

A prolonged QT interval on the electrocardiogram is associated with an increased risk of the torsades de pointes form of ventricular arrhythmia resulting in syncope, sudden cardiac arrest or death, or misdiagnosis as a seizure disorder. The cause of QT prolongation can be congenital and inherited as an autosomal dominant variant, or it can be transient and acquired, often because of QT-prolonging drugs or electrolyte abnormalities. Automated measurement of the QT interval can be inaccurate, especially when the baseline electrocardiogram is abnormal, and manual verification is recommended. In this clinical practice update we provide practical tips about measurement of the QT interval, diagnosis, and management of congenital long QT syndrome and acquired prolongation of the QT interval. For congenital long QT syndrome, certain ß-adrenergic-blocking drugs are highly effective, and implantable defibrillators are infrequently required. Many commonly prescribed drugs such as antidepressants and antibiotics can prolong the QT interval, and recommendations are provided on their safe use.

Management of massive and submassive pulmonary embolism, iliofemoral deep vein thrombosis, and chronic thromboembolic pulmonary hypertension: a scientific statement from the American Heart Association.

Venous thromboembolism (VTE) is responsible for the hospitalization of >250 000 Americans annually and represents a significant risk for morbidity and mortality. Despite the publication of evidence-based clinical practice guidelines to aid in the management of VTE in its acute and chronic forms, the clinician is frequently confronted with manifestations of VTE for which data are sparse and optimal management is unclear. In particular, the optimal use of advanced therapies for acute VTE, including thrombolysis and catheter-based therapies, remains uncertain. This report addresses the management of massive and submassive pulmonary embolism (PE), iliofemoral deep vein thrombosis (IFDVT),and chronic thromboembolic pulmonary hypertension (CTEPH). The goal is to provide practical advice to enable the busy clinician to optimize the management of patients with these severe manifestations of VTE. Although this document makes recommendations for management, optimal medical decisions must incorporate other factors, including patient wishes, quality of life, and life expectancy based on age and comorbidities. The appropriateness of these recommendations for a specific patient may vary depending on these factors and will be best judged by the bedside clinician.

Representation of Women in Atrial Fibrillation Clinical Practice Guidelines.

BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in men and women worldwide, and its prevalence is increasing. Management of AF is guided by evidence-based clinical practice guidelines which provide recommendations based on available evidence. The extent of sex-specific data in the AF literature used to provide guideline recommendations has not been investigated. Therefore, using the 2020 Canadian Cardiovascular Society (CCS) AF management guidelines as an example, the purpose of this study was to review female representation and the reporting of sex-disaggregated data in the studies referenced in AF guidelines. METHODS: Randomised controlled trials (RCTs) and prospective and retrospective cohorts were screened to calculate the proportion of study participants who were female and to establish whether studies provided sex-disaggregated analyses. The participant-prevalence ratio (PPR), a quotient of the female participant rate and the prevalence of women in the AF population, was calculated for each study. RESULTS: A total of 885 studies included in the CCS guidelines were considered. Of those, 467 met the inclusion criteria. Overall, women represented 39.1% of the population over all of the studies and RCTs had the lowest proportions of women (33.8%, PPR 0.70). Of studies with sex-disaggregated analyses (n = 140; 29.9%), single-centre RCTs and retrospective cohorts had the lowest and highest rates of sex-specific analyses, respectively (11.5% and 32.5%). CONCLUSIONS: The evidence used to derive guideline recommendations may be inadequate for sex-specific recommendations. Until enough data can support women-specific guidelines, increased inclusion of females in AF studies, may aid in the precision of recommendations.

Canadian Cardiovascular Society 2022 Guidelines for Peripheral Arterial Disease.

Patients with widespread atherosclerosis such as peripheral artery disease (PAD) have a high risk of cardiovascular and limb symptoms and complications, which affects their quality of life and longevity. Over the past 2 decades there have been substantial advances in diagnostics, pharmacotherapy, and interventions including endovascular and open surgical to aid in the management of PAD patients. To summarize the evidence regarding approaches to diagnosis, risk stratification, medical and intervention treatments for patients with PAD, guided by the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework, evidence was synthesized, and assessed for quality, and recommendations provided-categorized as weak or strong for each prespecified research question. Fifty-six recommendations were made, with 27% (15/56) graded as strong recommendations with high-quality evidence, 14% (8/56) were designated as strong recommendations with moderate-quality evidence, and 20% (11/56) were strong recommendations with low quality of evidence. Conversely 39% (22/56) were classified as weak recommendations. For PAD patients, strong recommendations on the basis of high-quality evidence, include smoking cessation interventions, structured exercise programs for claudication, lipid-modifying therapy, antithrombotic therapy with a single antiplatelet agent or dual pathway inhibition with low-dose rivaroxaban and aspirin; treatment of hypertension with an angiotensin converting enzyme or angiotensin receptor blocker; and for those with diabetes, a sodium-glucose cotransporter 2 inhibitor should be considered. Furthermore, autogenous grafts are more effective than prosthetic grafts for surgical bypasses for claudication or chronic limb-threatening ischemia involving the popliteal or distal arteries. Other recommendations indicated that new endovascular techniques and hybrid procedures be considered in patients with favourable anatomy and patient factors, and finally, the evidence for perioperative risk stratification for PAD patients who undergo surgery remains weak.

Carotid chemoreceptor modulation of blood flow during exercise in healthy humans.

Carotid chemoreceptor (CC) inhibition reduces sympathetic nervous outflow in exercising dogs and humans. We sought to determine if CC suppression increases muscle blood flow in humans during exercise and hypoxia. Healthy subjects (N = 13) were evaluated at rest and during constant-work leg extension exercise while exposed to either normoxia or hypoxia (inspired O(2) tension, F(IO(2)), ≈ 0.12, target arterial O(2) saturation = 85%). Subjects breathed hyperoxic gas (F(IO(2)) ≈ 1.0) and/or received intravenous dopamine to inhibit the CC while femoral arterial blood flow data were obtained continuously with pulsed Doppler ultrasound. Exercise increased heart rate, mean arterial pressure, femoral blood flow and conductance compared to rest. Transient hyperoxia had no significant effect on blood flow at rest, but increased femoral blood flow and conductance transiently during exercise without changing blood pressure. Similarly, dopamine had no effect on steady-state blood flow at rest, but increased femoral blood flow and conductance during exercise. The transient vasodilatory response observed by CC inhibition with hyperoxia during exercise could be blocked with simultaneous CC inhibition with dopamine. Despite evidence of dopamine reducing ventilation during hypoxia, no effect on femoral blood flow, conductance or mean arterial pressure was observed either at rest or during exercise with CC inhibition with dopamine while breathing hypoxia. These findings indicate that the carotid chemoreceptor contributes to skeletal muscle blood flow regulation during normoxic exercise in healthy humans, but that the influence of the CC on blood flow regulation in hypoxia is limited.

The Many Care Models to Treat Thoracic Aortic Disease in Canada: A Nationwide Survey of Cardiac Surgeons, Cardiologists, Interventional Radiologists, and Vascular Surgeons.

BACKGROUND: Several specialties treat thoracic aortic disease, resulting in multiple patient care pathways. This study aimed to characterize these varied care models to guide health policy. METHODS: A 57-question e-survey was sent to staff cardiac surgeons, cardiologists, interventional radiologists, and vascular surgeons at 7 Canadian medical societies. RESULTS: For 914 physicians, the response rate was 76% (86 of 113) for cardiac surgeons, 40% (58 of 146) for vascular surgeons, 24% (34 of 140) for radiologists, and 14% (70 of 515) for cardiologists. Several services admitted type B dissections (vascular 37%, cardiology 31%, cardiac 18%, other 7%), and care was heterogeneous. Ownership of disease management was overestimated relative to the perspective of the other specialties. Type A dissection admissions and treatment were more uniform, but emergent call coverage varied. A 24/7 aortic specialist on-call schedule was present only 4% of the time. "Aortic" case rounds promoted attendance by a broader aortic specialty contingency relative to rounds that were specialty specific. Although 89% of respondents felt an aortic team was best for patient care, only 54% worked at an institution with an aortic team present, and only 28% utilized an aortic clinic. Questions designed to define an aortic team derived 63 different combinations. CONCLUSIONS: Thoracic aortic disease follows a network of undefined and variable care pathways, despite its high-risk population in need of complex treatment considerations. Multidisciplinary aortic teams and clinics exist in low volume, and the "aortic team" remains an obscure construct. A multispecialty initiative to define the aortic team and outline standardized navigation pathways within the health systems hospitals is advocated.

CONTEXTE: La prise en charge de la maladie de l'aorte thoracique peut faire appel à plusieurs spécialités, ce qui a pour effet de multiplier les trajectoires de soins des patients. Cette étude visait à caractériser ces différents modèles de soins afin d'éclairer l'élaboration des politiques de santé. MÉTHODOLOGIE: Un sondage électronique de 57 questions a été envoyé aux chirurgiens cardiaques, aux cardiologues, aux radiologistes interventionnels et aux chirurgiens vasculaires membres de 7 associations médicales canadiennes. RÉSULTATS: Sur un total de 914 médecins, le taux de réponse a été de 76 % (86 sur 113) chez les chirurgiens cardiaques, de 40 % (58 sur 146) chez les chirurgiens vasculaires, de 24 % (34 sur 140) chez les radiologistes et de 14 % (70 sur 515) chez les cardiologues. Plusieurs services avaient admis des cas de dissection aortique de type B (chirurgie vasculaire 37 %, cardiologie 31 %, chirurgie cardiaque 18 %, autre 7 %) et les soins étaient hétérogènes. Les spécialistes surestimaient leur responsabilité de la prise en charge des cas par rapport à celle des autres spécialistes. Les admissions de cas de dissection de type A et leur traitement étaient plus uniformes, mais la présence de spécialistes de garde pouvant traiter les cas urgents était variable. La présence continue d'un spécialiste de l'aorte de garde n'était observée que pendant 4 % du temps. Les séances de discussion de cas « aortiques ¼ favorisaient la participation par une gamme plus large de spécialistes de l'aorte que les discussions axées sur une spécialité donnée. Si 89 % des répondants estimaient qu'une équipe « aortique ¼ était la meilleure option pour les soins aux patients, ils n'étaient que 54 % à travailler dans un établissement disposant d'une telle équipe et 28 % à utiliser les services d'une clinique de l'aorte. En réponse aux questions portant sur les éléments constitutifs d'une équipe aortique, 63 combinaisons différentes de spécialités ont été proposées. CONCLUSIONS: La prise en charge de la maladie de l'aorte thoracique emprunte un dédale de trajectoires de soins non définies et variables, alors que sa population à haut risque a besoin de traitements complexes. Les équipes multidisciplinaires et les cliniques spécialisées dans le traitement de l'aorte sont rares, et la notion d' « équipe aortique ¼ demeure un concept obscur. Nous préconisons une initiative réunissant des spécialistes de différents domaines pour définir les éléments constitutifs d'une équipe aortique et établir des trajectoires de navigation normalisées au sein des hôpitaux du système de santé.

The Effect of Carotid Chemoreceptor Inhibition on Exercise Tolerance in Chronic Heart Failure.

PURPOSE: Chronic heart failure (CHF) is characterized by heightened sympathetic nervous activity, carotid chemoreceptor (CC) sensitivity, marked exercise intolerance and an exaggerated ventilatory response to exercise. The purpose of this study was to determine the effect of CC inhibition on exercise cardiovascular and ventilatory function, and exercise tolerance in health and CHF. METHODS: Twelve clinically stable, optimally treated patients with CHF (mean ejection fraction: 43 ± 2.5%) and 12 age- and sex-matched healthy controls were recruited. Participants completed two time-to-symptom-limitation (TLIM) constant load cycling exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 µg⋅kg-1⋅min-1; order randomized). Ventilation was measured using expired gas data and operating lung volume data were determined during exercise by inspiratory capacity maneuvers. Cardiac output was estimated using impedance cardiography, and vascular conductance was calculated as cardiac output/mean arterial pressure. RESULTS: There was no change in TLIM in either group with dopamine (CHF: saline 13.1 ± 2.4 vs. dopamine 13.5 ± 1.6 min, p = 0.78; Control: saline 10.3 ± 1.2 vs. dopamine 11.5 ± 1.3 min, p = 0.16). In CHF patients, dopamine increased cardiac output (p = 0.03), vascular conductance (p = 0.01) and oxygen delivery (p = 0.04) at TLIM, while ventilatory parameters were unaffected (p = 0.76). In controls, dopamine improved vascular conductance at TLIM (p = 0.03), but no other effects were observed. CONCLUSION: Our findings suggest that the CC contributes to cardiovascular regulation during full-body exercise in patients with CHF, however, CC inhibition does not improve exercise tolerance.

Temporal and spatial effect of air pollution on hospital admissions for myocardial infarction: a case-crossover study.

BACKGROUND: In studies showing associations between ambient air pollution and myocardial infarction (MI), data have been lacking on the inherent spatial variability of air pollution. The aim of this study was to determine whether the long-term spatial distribution of air pollution influences short-term temporal associations between air pollution and admission to hospital for MI. METHODS: We identified adults living in Calgary who were admitted to hospital for an MI between 2004 and 2012. We evaluated associations between short-term exposure to air pollution (ozone [O3], nitrogen dioxide [NO2], sulfur dioxide [SO2], carbon monoxide [CO], particulate matter < 10 µm in diameter [PM10] and particulate matter < 2.5 µm in diameter [PM2.5]), and hospital admissions for MI using a time-stratified, case-crossover study design. Air Quality Health Index (AQHI) scores were calculated from a composition of O3, NO2 and PM2.5. Conditional logistic regression models were stratified by low, medium and high levels of neighbourhood NO2 concentrations derived from land use regression models; results of these analyses are presented as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: From 2004 to 2012, 6142 MIs were recorded in Calgary. Individuals living in neighbourhoods with higher long-term air pollution concentrations were more likely to be admitted to hospital for MI after short-term elevations in air pollution (e.g., 5-day average NO2: OR 1.20, 95% CI 1.03-1.40, per interquartile range [IQR]) as compared with regions with lower air pollution (e.g., 5-day average NO2: OR 0.90, 95% CI 0.78-1.04, per IQR). In high NO2 tertiles, the AQHI score was associated with MI (e.g., 5-day average OR 1.13, 95% CI 1.02-1.24, per IQR; 3-day average OR 1.13, 95% CI 1.04-1.23, per IQR). INTERPRETATION: Our results show that the effect of air pollution on hospital admissions for MI was stronger in areas with higher NO2 concentrations than that in areas with lower NO2 concentrations. Individuals living in neighbourhoods with higher traffic-related pollution should be advised of the health risks and be attentive to special air quality warnings.

The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive Guidelines for the Management of Atrial Fibrillation.

The Canadian Cardiovascular Society (CCS) atrial fibrillation (AF) guidelines program was developed to aid clinicians in the management of these complex patients, as well as to provide direction to policy makers and health care systems regarding related issues. The most recent comprehensive CCS AF guidelines update was published in 2010. Since then, periodic updates were published dealing with rapidly changing areas. However, since 2010 a large number of developments had accumulated in a wide range of areas, motivating the committee to complete a thorough guideline review. The 2020 iteration of the CCS AF guidelines represents a comprehensive renewal that integrates, updates, and replaces the past decade of guidelines, recommendations, and practical tips. It is intended to be used by practicing clinicians across all disciplines who care for patients with AF. The Grading of Recommendations, Assessment, Development and Evaluations (GRADE) system was used to evaluate recommendation strength and the quality of evidence. Areas of focus include: AF classification and definitions, epidemiology, pathophysiology, clinical evaluation, screening and opportunistic AF detection, detection and management of modifiable risk factors, integrated approach to AF management, stroke prevention, arrhythmia management, sex differences, and AF in special populations. Extensive use is made of tables and figures to synthesize important material and present key concepts. This document should be an important aid for knowledge translation and a tool to help improve clinical management of this important and challenging arrhythmia.

Sex-Specific Considerations in Guidelines Generation and Application.

New knowledge about male-female differences in pathophysiology, diagnosis, and treatment is shifting the practice of medicine from a one-size-fits all approach to a more individualized process that considers sex-specific interventions at the point of care. In this article, we review how clinical practice guideline committees can incorporate a structured framework to determine whether sex-specific assessments of the quality of the evidence or the particular recommendations should be made. The process can be operationalized by societies who author clinical practice guidelines by developing formal policies to approach biological sex in a systematic way, and by ensuring that writing committees include an individual who will champion the formal appraisal of the literature for associations between sex and the outcomes of interest. Ongoing challenges are discussed, and solutions are provided for how to disaggregate the evidence, how to assess bias, how to improve search strategies, and what to do when the data are insufficient to make sex-specific recommendations. Application of sex-specific recommendations will involve routinely asking whether the presentation, diagnostic workup, or management might change for each patient if they were the opposite sex.

Safe Cardioversion for Patients With Acute-Onset Atrial Fibrillation and Flutter: Practical Concerns and Considerations.

In this Viewpoint concerns raised by Canadian emergency physicians regarding recommendations 2 and 6 from the recent Canadian Cardiovascular Society 2018 update for atrial fibrillation are discussed. These recommendations narrow the window for safe cardioversion and suggest 4 weeks of anticoagulation for all patients who undergo urgent cardioversion regardless of their CHADS-65 status. We discuss the implications of Grading of Recommendations, Assessment, Development, and Evaluation weak recommendations on the basis of low-quality evidence.

Cardiac rehabilitation in people with peripheral arterial disease: A higher risk population that benefits from completion.

BACKGROUND: Peripheral arterial disease (PAD) is common in people referred for cardiac rehabilitation (CR). However, the associations between PAD diagnosis and CR attendance and mortality remain to be defined. METHODS: All patients referred to a 12-week exercise-based CR program were included. Associations between PAD diagnosis and starting CR as well as between PAD diagnosis and completing CR were measured using multivariable logistic regression. Associations between CR completion and mortality were measured using adjusted Cox proportional hazards models, and a propensity-based matching sensitivity analysis was performed. RESULTS: 23,215 patients (mean age 61.3 years; 21.6% female) were referred to CR; 1366 (5.9%) had PAD. Those with PAD were less likely to start CR (57.0% vs 68.2%, adjusted OR 0.81, 95%CI 0.72, 0.91) and complete CR if they started (70.6% vs 76.7%, adjusted OR 0.80, 95%CI 0.68, 0.94). Patients with PAD completing CR had lower exercise capacity at baseline (6.6 vs. 7.6 METs, p < 0.0001) and completion (7.5 vs 8.6 METs, p < 0.0001). There were 3510 deaths over follow-up; 10-year survival was lower in those with PAD (66.9 vs 84.5%; p < 0.0001). CR completion was associated with lower mortality for all (adjusted HR 0.62 (95%CI 0.57, 0.67)), and the magnitude of the association was independent of PAD status. CONCLUSIONS: Patients with PAD referred to CR had a higher mortality than those without, and were less likely to start and complete CR. Completion of CR was associated with improved fitness and survival for PAD patients. These data support broader use of CR by those with PAD.

Physiological Association between Limb Ballistocardiogram and Arterial Blood Pressure Waveforms: A Mathematical Model-Based Analysis.

By virtue of its direct association with the cardiovascular (CV) functions and compatibility to unobtrusive measurement during daily activities, the limb ballistocardiogram (BCG) is receiving an increasing interest as a viable means for ultra-convenient CV health and disease monitoring. However, limited insights on its physical implications have hampered disciplined interpretation of the BCG and systematic development of the BCG-based approaches for CV health monitoring. In this study, a mathematical model that can predict the limb BCG in responses to the arterial blood pressure (BP) waves in the aorta was developed and experimentally validated. The validated mathematical model suggests that (i) the limb BCG waveform reveals the timings and amplitudes associated with the aortic BP waves; (ii) mechanical filtering exerted by the musculoskeletal properties of the body can obscure the manifestation of the arterial BP waves in the limb BCG; and (iii) the limb BCG exhibits meaningful morphological changes in response to the alterations in the CV risk predictors. The physical insights garnered by the analysis of the mathematical model may open up new opportunities toward next generation of the BCG-based CV healthcare techniques embedded with transparency, interpretability, and robustness against the external variability.

The effect of carotid chemoreceptor inhibition on exercise tolerance in chronic obstructive pulmonary disease: A randomized-controlled crossover trial.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) have an exaggerated ventilatory response to exercise, contributing to exertional dyspnea and exercise intolerance. We recently demonstrated enhanced activity and sensitivity of the carotid chemoreceptor (CC) in COPD which may alter ventilatory and cardiovascular regulation and negatively affect exercise tolerance. We sought to determine whether CC inhibition improves ventilatory and cardiovascular regulation, dyspnea and exercise tolerance in COPD. METHODS: Twelve mild-moderate COPD patients (FEV1 83 ±â€¯15 %predicted) and twelve age- and sex-matched healthy controls completed two time-to-symptom limitation (TLIM) constant load exercise tests at 75% peak power output with either intravenous saline or low-dose dopamine (2 µg·kg-1·min-1, order randomized) to inhibit the CC. Ventilatory responses were evaluated using expired gas data and dyspnea was evaluated using a modified Borg scale. Inspiratory capacity maneuvers were performed to determine operating lung volumes. Cardiac output was estimated using impedance cardiography and vascular conductance was calculated as cardiac output/mean arterial pressure (MAP). RESULTS: At a standardized exercise time of 4-min and at TLIM; ventilation, operating volumes and dyspnea were unaffected by dopamine in COPD patients and controls. In COPD, dopamine decreased MAP and increased vascular conductance at all time points. In controls, dopamine increased vascular conductance at TLIM, while MAP was unaffected. CONCLUSION: There was no change in time to exhaustion in either group with dopamine. These data suggest that the CC plays a role in cardiovascular regulation during exercise in COPD; however, ventilation, dyspnea and exercise tolerance were unaffected by CC inhibition in COPD patients.

Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is characterized by genetic and acquired abnormalities that suppress apoptosis and enhance cell proliferation in the vascular wall, including downregulation of the bone morphogenetic protein axis and voltage-gated K+ (Kv) channels. Survivin is an "inhibitor of apoptosis" protein, previously thought to be expressed primarily in cancer cells. We found that survivin was expressed in the pulmonary arteries (PAs) of 6 patients with PAH and rats with monocrotaline-induced PAH, but not in the PAs of 3 patients and rats without PAH. Gene therapy with inhalation of an adenovirus carrying a phosphorylation-deficient survivin mutant with dominant-negative properties reversed established monocrotaline-induced PAH and prolonged survival by 25%. The survivin mutant lowered pulmonary vascular resistance, RV hypertrophy, and PA medial hypertrophy. Both in vitro and in vivo, inhibition of survivin induced PA smooth muscle cell apoptosis, decreased proliferation, depolarized mitochondria, caused efflux of cytochrome c in the cytoplasm and translocation of apoptosis-inducing factor into the nucleus, and increased Kv channel current; the opposite effects were observed with gene transfer of WT survivin, both in vivo and in vitro. Inhibition of the inappropriate expression of survivin that accompanies human and experimental PAH is a novel therapeutic strategy that acts by inducing vascular mitochondria-dependent apoptosis.

2018 Focused Update of the Canadian Cardiovascular Society Guidelines for the Management of Atrial Fibrillation.

The Canadian Cardiovascular Society (CCS) Atrial Fibrillation Guidelines Committee provides periodic reviews of new data to produce focused updates that address clinically important advances in atrial fibrillation (AF) management. This 2018 Focused Update addresses: (1) anticoagulation in the context of cardioversion of AF; (2) the management of antithrombotic therapy for patients with AF in the context of coronary artery disease; (3) investigation and management of subclinical AF; (4) the use of antidotes for the reversal of non-vitamin K antagonist oral anticoagulants; (5) acute pharmacological cardioversion of AF; (6) catheter ablation for AF, including patients with concomitant AF and heart failure; and (7) an integrated approach to the patient with AF and modifiable cardiovascular risk factors. The recommendations were developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) standards. Individual studies and literature were reviewed for quality and bias; the literature review process and evidence tables are included as Supplementary Material and are available on the CCS Web site. Details of the updated recommendations are presented, along with their background and rationale. This document is linked to an updated summary of all CCS AF guidelines recommendations, from 2010 to the present 2018 Focused Update, which is provided in the Supplementary Material.

An abnormal mitochondrial-hypoxia inducible factor-1alpha-Kv channel pathway disrupts oxygen sensing and triggers pulmonary arterial hypertension in fawn hooded rats: similarities to human pulmonary arterial hypertension.

BACKGROUND: The cause of pulmonary arterial hypertension (PAH) was investigated in humans and fawn hooded rats (FHR), a spontaneously pulmonary hypertensive strain. METHODS AND RESULTS: Serial Doppler echocardiograms and cardiac catheterizations were performed in FHR and FHR/BN1, a consomic control that is genetically identical except for introgression of chromosome 1. PAH began after 20 weeks of age, causing death by &60 weeks. FHR/BN1 did not develop PAH. FHR pulmonary arterial smooth muscle cells (PASMCs) had a rarified reticulum of hyperpolarized mitochondria with reduced expression of electron transport chain components and superoxide dismutase-2. These mitochondrial abnormalities preceded PAH and persisted in culture. Depressed mitochondrial reactive oxygen species (ROS) production caused normoxic activation of hypoxia inducible factor (HIF-1alpha), which then inhibited expression of oxygen-sensitive, voltage-gated K+ channels (eg, Kv1.5). Disruption of this mitochondrial-HIF-Kv pathway impaired oxygen sensing (reducing hypoxic pulmonary vasoconstriction, causing polycythemia), analogous to the pathophysiology of chronically hypoxic Sprague-Dawley rats. Restoring ROS (exogenous H2O2) or blocking HIF-1alpha activation (dominant-negative HIF-1alpha) restored Kv1.5 expression/function. Dichloroacetate, a mitochondrial pyruvate dehydrogenase kinase inhibitor, corrected the mitochondrial-HIF-Kv pathway in FHR-PAH and human PAH PASMCs. Oral dichloroacetate regressed FHR-PAH and polycythemia, increasing survival. Chromosome 1 genes that were dysregulated in FHRs and relevant to the mitochondria-HIF-Kv pathway included HIF-3alpha (an HIF-1alpha repressor), mitochondrial cytochrome c oxidase, and superoxide dismutase-2. Like FHRs, human PAH-PASMCs had dysmorphic, hyperpolarized mitochondria; normoxic HIF-1alpha activation; and reduced expression/activity of HIF-3alpha, cytochrome c oxidase, and superoxide dismutase-2. CONCLUSIONS: FHRs have a chromosome 1 abnormality that disrupts a mitochondria-ROS-HIF-Kv pathway, leading to PAH. Similar abnormalities occur in idiopathic human PAH. This study reveals an intersection between oxygen-sensing mechanisms and PAH. The mitochondria-ROS-HIF-Kv pathway offers new targets for PAH therapy.