M. Sean McMurtry

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.

Focused 2012 Update of the Canadian Cardiovascular Society Atrial Fibrillation Guidelines: Recommendations for Stroke Prevention and Rate/Rhythm Control

The Canadian Cardiovascular Society (CCS) published the complete set of 2010 Atrial Fibrillation (AF) Guidelines in the January, 2011 issue of the Canadian Journal of Cardiology. During its deliberations, the CCS Guidelines Committee engaged to a timely review of future evidence, with periodic composition of focused updates to address clinically important advances. In 2011, results were published from 3 pivotal AF trials: the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF), the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study, and the Permanent Atrial Fibrillation Outcome Study Using Dronedarone on Top of Standard Therapy (PALLAS), comparing dronedarone with placebo in patients with permanent AF and additional cardiovascular disease risk-factor burden. Each of these large randomized trials provided clear results with major implications for AF management. Other important evidence that has emerged since the 2010 Guidelines includes findings about prediction instruments for AF-associated stroke and bleeding risk, stroke risk in paroxysmal-AF patients, risk-benefit considerations related to oral anticoagulation in patients with chronic kidney disease, and risk/benefit considerations in the use of antiplatelet agents, alone and in combination with each other or with oral anticoagulants, in AF patients. The Guidelines Committee judged that this extensive and important new evidence required focused updating of the 2010 Guidelines with respect to stroke prevention and rate/rhythm control. This report presents the details of the new recommendations, along with the background and rationale.

An Abnormal Mitochondrial–Hypoxia Inducible Factor-1α–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-1&agr;), 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-1&agr; activation (dominant-negative HIF-1&agr;) 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-3&agr; (an HIF-1&agr; repressor), mitochondrial cytochrome c oxidase, and superoxide dismutase-2. Like FHRs, human PAH-PASMCs had dysmorphic, hyperpolarized mitochondria; normoxic HIF-1&agr; activation; and reduced expression/activity of HIF-3&agr;, 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.

Dichloroacetate Prevents and Reverses Pulmonary Hypertension by Inducing Pulmonary Artery Smooth Muscle Cell Apoptosis

The pulmonary arteries (PA) in pulmonary arterial hypertension (PAH) are constricted and remodeled;. They have suppressed apoptosis, partly attributable to suppression of the bone morphogenetic protein axis and selective downregulation of PA smooth muscle cell (PASMC) voltage-gated K+ channels, including Kv1.5. The Kv downregulation-induced increase in [K+]i, tonically inhibits caspases, further suppressing apoptosis. Mitochondria control apoptosis and produce activated oxygen species like H2O2, which regulate vascular tone by activating K+ channels, but their role in PAH is unknown. We show that dichloroacetate (DCA), a metabolic modulator that increases mitochondrial oxidative phosphorylation, prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality. Compared with MCT-PAH, DCA-treated rats (80 mg/kg per day in drinking water on day 14 after MCT, studied on day 21) have decreased pulmonary, but not systemic, vascular resistance (63% decrease, P<0.002), PA medial thickness (28% decrease, P<0.0001), and right ventricular hypertrophy (34% decrease, P<0.001). DCA is similarly effective when given at day 1 or day 21 after MCT (studied day 28) but has no effect on normal rats. DCA depolarizes MCT-PAH PASMC mitochondria and causes release of H2O2 and cytochrome c, inducing a 10-fold increase in apoptosis within the PA media (TUNEL and caspase 3 activity) and decreasing proliferation (proliferating-cell nuclear antigen and BrdU assays). Immunoblots, immunohistochemistry, laser-captured microdissection-quantitative reverse-transcription polymerase chain reaction and patch-clamping show that DCA reverses the Kv1.5 downregulation in resistance PAs. In summary, DCA reverses PA remodeling by increasing the mitochondria-dependent apoptosis/proliferation ratio and upregulating Kv1.5 in the media. We identify mitochondria-dependent apoptosis as a potential target for therapy and DCA as an effective and selective treatment for PAH.

In Vivo Gene Transfer of the O2-Sensitive Potassium Channel Kv1.5 Reduces Pulmonary Hypertension and Restores Hypoxic Pulmonary Vasoconstriction in Chronically Hypoxic Rats

Background—Alveolar hypoxia acutely elicits pulmonary vasoconstriction (HPV). Chronic hypoxia (CH), despite attenuating HPV, causes pulmonary hypertension (CH-PHT). HPV results, in part, from inhibition of O2-sensitive, voltage-gated potassium channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). CH decreases Kv channel current/expression and depolarizes and causes Ca2+ overload in PASMCs. We hypothesize that Kv gene transfer would normalize the pulmonary circulation (restore HPV and reduce CH-PHT), despite ongoing hypoxia. Methods and Results—Adult male Sprague-Dawley rats were exposed to normoxia or CH for 3 to 4 weeks and then nebulized orotracheally with saline or adenovirus (Ad5) carrying genes for the reporter, green fluorescent protein reporter±human Kv1.5 (cloned from normal PA). HPV was assessed in isolated lungs. Hemodynamics, including Fick and thermodilution cardiac output, were measured in vivo 3 and 14 days after gene therapy by use of micromanometer-tipped catheters. Transgene expression, measured by quantitative RT-PCR, was confined to the lung, persisted for 2 to 3 weeks, and did not alter endogenous Kv1.5 levels. Ad5-Kv1.5 caused no mortality or morbidity, except for sporadic, mild elevation of liver transaminases. Ad5-Kv1.5 restored the O2-sensitive K+ current of PASMCs, normalized HPV, and reduced pulmonary vascular resistance. Pulmonary vascular resistance decreased at day 2 because of increased cardiac output, and remained reduced at day 14, at which time there was concomitant regression of right ventricular hypertrophy and PA medial hypertrophy. Conclusions—Kv1.5 is an important O2-sensitive channel and potential therapeutic target in PHT. Kv1.5 gene therapy restores HPV and improves PHT. This is, to the best of our knowledge, the first example of K+ channel gene therapy for a vascular disease.

Preferential Expression and Function of Voltage-Gated, O2-Sensitive K+ Channels in Resistance Pulmonary Arteries Explains Regional Heterogeneity in Hypoxic Pulmonary Vasoconstriction: Ionic Diversity in Smooth Muscle Cells

Hypoxic pulmonary vasoconstriction (HPV) is initiated by inhibition of O2-sensitive, voltage-gated (Kv) channels in pulmonary arterial smooth muscle cells (PASMCs). Kv inhibition depolarizes membrane potential (EM), thereby activating Ca2+ influx via voltage-gated Ca2+ channels. HPV is weak in extrapulmonary, conduit pulmonary arteries (PA) and strong in precapillary resistance arteries. We hypothesized that regional heterogeneity in HPV reflects a longitudinal gradient in the function/expression of PASMC O2-sensitive Kv channels. In adult male Sprague Dawley rats, constrictions to hypoxia, the Kv blocker 4-aminopyridine (4-AP), and correolide, a Kv1.x channel inhibitor, were endothelium-independent and greater in resistance versus conduit PAs. Moreover, HPV was dependent on Kv-inhibition, being completely inhibited by pretreatment with 4-AP. Kv1.2, 1.5, Kv2.1, Kv3.1b, Kv4.3, and Kv9.3. mRNA increased as arterial caliber decreased; however, only Kv1.5 protein expression was greater in resistance PAs. Resistance PASMCs had greater K+ current (IK) and a more hyperpolarized EM and were uniquely O2− and correolide-sensitive. The O2-sensitive current (active at −65 mV) was resistant to iberiotoxin, with minimal tityustoxin sensitivity. In resistance PASMCs, 4-AP and hypoxia inhibited IK 57% and 49%, respectively, versus 34% for correolide. Intracellular administration of anti-Kv1.5 antibodies inhibited correolide’s effects. The hypoxia-sensitive, correolide-insensitive IK (15%) was conducted by Kv2.1. Anti-Kv1.5 and anti-Kv2.1 caused additive depolarization in resistance PASMCs (Kv1.5>Kv2.1) and inhibited hypoxic depolarization. Heterologously expressed human PASMC Kv1.5 generated an O2− and correolide-sensitive IK like that in resistance PASMCs. In conclusion, Kv1.5 and Kv2.1 account for virtually all the O2-sensitive current. HPV occurs in a Kv-enriched resistance zone because resistance PASMCs preferentially express O2-sensitive Kv-channels.

Canadian Cardiovascular Society Position Statement on the Management of Thoracic Aortic Disease

This Canadian Cardiovascular Society position statement aims to provide succinct perspectives on key issues in the management of thoracic aortic disease (TAD). This document is not a comprehensive overview of TAD and important elements of the epidemiology, presentation, diagnosis, and management of acute aortic syndromes are deliberately not discussed; readers are referred to the 2010 guidelines published by the American Heart Association, American College of Cardiology, American Association for Thoracic Surgery, and other stakeholders. Rather, this document is a practical guide for clinicians managing adult patients with TAD. Topics covered include size thresholds for surgical intervention, emerging therapies, imaging modalities, medical and lifestyle management, and genetics of TAD. The primary panel consisted of experts from a variety of disciplines that are essential for comprehensive management of TAD patients. The methodology involved a focused literature review with an emphasis on updates since 2010 and the use of Grading of Recommendations Assessment, Development, and Evaluation methodology to arrive at specific recommendations. The final document then underwent review by a secondary panel. This document aims to provide recommendations for most patients and situations. However, the ultimate judgement regarding the management of any individual patients should be made by their health care team.

Stroke Prevention in Atrial Fibrillation Patients With Chronic Kidney Disease

Chronic kidney disease (CKD) is prevalent in elderly patients with atrial fibrillation and is an independent risk factor for stroke. Warfarin anticoagulation is efficacious for stroke prevention in atrial fibrillation patients with moderate CKD (stage III, estimated glomerular filtration rate 30-59 mL/min), but recent observational studies have challenged its value for patients with end-stage renal disease requiring dialysis. The novel oral anticoagulants (i.e., dabigatran, apixaban, rivaroxaban) all undergo renal metabolism to varying degrees, and hence dosing, efficacy, and safety require special consideration in CKD patients. In randomized trials to date involving 11,169 patients with moderate CKD, the novel oral anticoagulants performed well, with similar efficacy and safety profiles as for non-CKD patients. For atrial fibrillation patients with stage III CKD, the available data are strongest for dabigatran 150 mg twice daily as superior to warfarin for stroke prevention and for apixaban as superior to warfarin regarding reduced major hemorrhage. Renal function should be monitored at least annually in patients receiving a novel oral anticoagulant, and more often in elderly patients and those with underlying CKD or comorbidities who are at special risk for dehydration and deterioration of renal function. Much remains to be learned about the optimal use of the novel oral anticoagulants in CKD patients; additional studies about optimal dosing of the novel oral anticoagulants and frequency of monitoring renal function in CKD patients with atrial fibrillation are needed. Anticoagulation options for hemodialysis patients require testing in randomized trials.

Do women bleed more than men when prescribed novel oral anticoagulants for venous thromboembolism? A sex-based meta-analysis

INTRODUCTION Bleeding complications occur more frequently in women than men in clinical trials of warfarin and thrombolytics. It is unknown whether these sex-related differences exist for new oral anticoagulants, including dabigatran, rivaroxaban, and apixaban. To determine whether women suffer more bleeding complications with these agents, we conducted a systematic review and meta-analysis of randomized controlled trials on new oral anticoagulants for venous thromboembolism (VTE). MATERIALS AND METHODS Medline, Embase, and the Cochrane-controlled trial register on the Cochrane library were searched to identify studies that evaluated novel oral anticoagulants versus any comparator, and reported outcomes, including major bleeding and recurrent VTE, stratified by sex. No language restrictions were applied. Studies were evaluated according to a priori inclusion criteria and critically appraised using established internal validity criteria. Pooled relative risk was estimated using a random effects model. RESULTS Eight studies were eligible, comprising 9417 patients. There was no difference in the primary efficacy outcome of recurrent VTE between men and women [Relative Risk (RR) 1.02, 95% confidence interval (CI) 0.74-1.39]. However, men had less major bleeding with novel oral anticoagulants compared to women [RR 0.79, 95% CI 0.66-0.97, p=0.03]. All-cause mortality was not reported by sex in any of the studies. CONCLUSION Women suffer more bleeding complications than men when receiving novel oral anticoagulants for VTE. Future clinical trials should report outcomes stratified by sex, and further studies are needed to investigate the clinical impact of this sex-related safety difference.

Secular Trends in Incidence and Mortality of Acute Venous Thromboembolism: The AB-VTE Population-Based Study

BACKGROUND Venous thromboembolism is a major cause of morbidity and mortality, and comprehensive studies profiling the epidemiology and pattern of health services use are needed. In this study we provide contemporary estimates of venous thromboembolism incidence and case fatality over the past decade. METHODS We developed a population-based venous thromboembolism dataset by linking 6 administrative health databases in Alberta, Canada from April 1, 2002 to March 31, 2012. We defined acute symptomatic cases using a validated algorithm and used Poisson regression to model annual venous thromboembolism counts. RESULTS We identified 31,656 cases of acute symptomatic venous thromboembolism between April 1, 2002 and March 31, 2012. The age- and sex-adjusted incidence rate of venous thromboembolism was 1.38 (95% confidence interval [CI], 1.37-1.40) per 1000 person-years. For pulmonary embolism it was 0.38 (95% CI, 0.36-0.40) per 1000 person-years, and for deep vein thrombosis it was 1.0 (95% CI, 0.99-1.1) per 1000 person-years. The adjusted model showed no significant change in the incidence of venous thromboembolism during the study period. The 30-day case fatality rate of venous thromboembolism was 2.0% (95% CI, 1.89-2.21) and was almost doubled in patients with pulmonary embolism: 3.9% (95% CI, 3.50-4.33). The 1-year case fatality rate was 9.2% (95% CI, 8.88-9.52) for venous thromboembolism and 12.9% (95% CI, 12.2-13.6) for patients with pulmonary embolism. The case fatality rate increased with increasing subject age. The 1-year and 5-year survivals after first acute venous thromboembolism were similar in patients with unprovoked and provoked events. However, in patients with cancer-associated thrombosis, the 1-year and 5-year survival rate was 66% (95% CI, 64.71%-67.29%) and 46% (95% CI, 43.28%-48.72%), respectively. CONCLUSION The incidence of acute venous thromboembolism remained unchanged over a 10-year period. However, the case fatality of venous thromboembolism is substantial.